Dr Iwan tem Cell Therapy Information Center (continiu)

Regrow or Repair: Potential Regenerative Therapies for the Kidney

 

Even if an adult stem cell population does exist in the adult kidney, would it remain in an end-stage kidney?

 

Indeed, the adoption of any organ-based cellular therapy is likely to succeed only if chronic renal disease can be diagnosed early and if such therapies are implemented well before end-stage renal failure is reached.

 

As we move closer to that point in time, the ethical debate about whether trials can proceed before ESRD will become critical.

 

 A lack of surrogate end points with which to assess the success of a cellular therapy in renal disease will make clinical trails long and expensive, eroding the will of the developers to continue to support the trials.

 

Read the studies report below

 

  1. 1.       Melissa H. Little

+Author Affiliations

  1. Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
  2. Address correspondence to:
    Prof. Melissa H. Little, Institute for Molecular Bioscience, Queensland Bioscience Precinct, University of Queensland, St. Lucia, Brisbane, Qld, 4072, Australia. Phone: +61-7-3346-2054; Fax: +61-7-3346-2101;m.little@imb.uq.edu.au; Web: www.imb.uq.edu.au

Next Section

 

Abstract

Regenerative medicine is being heralded in a similar way as gene therapy was some 15 yr ago. It is an area of intense excitement and potential, as well as myth and disinformation. However, with the increasing rate of end-stage renal failure and limited alternatives for its treatment, we must begin to investigate seriously potential regenerative approaches for the kidney. This review defines which regenerative options there might be for renal disease, summarizes the progress that has been made to date, and investigates some of the unique obstacles to such treatments that the kidney presents. The options discussed include in situ organ repair via bone marrow recruitment or dedifferentiation;ex vivo stem cell therapies, including both autologous and nonautologous options; and bioengineering approaches for the creation of a replacement organ.

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Regenerative Approaches to Renal Disease

The term regenerative medicine straddles cell biology, matrix biology, and bioengineering with the objective to regrow or repair a damaged organ or tissue type. It can be defined as the use of cells for the treatment of disease and encompasses both organ repair and the de novo regeneration of an entire organ

Organ repair can be delivered in situ or ex vivo.

 

The simplest and most pharmacologically attractive strategy for organ repair in situ is the delivery of a soluble reparative factor that improves the ability of the kidney to repair itself.

 

Although such an approach may involve the understanding of the factors that are produced by stem cells, this is not a cellular therapy and is not dealt with in this review.

Other in situ possibilities include the recruitment of stem cells to the kidney to elicit repair and the induction of dedifferentiation of resident renal cells.

 

Whereas some regard in situ approaches as more likely to be successful for an architecturally and anatomically constrained organ such as the kidney, the other approach is the ex vivo culture of stem cells for redelivery to the damaged kidney.

 

This might involve autologous or nonautologous stem cells from a variety of sources. Finally, a bioengineering approach that relies on cells, factors, and matrix may be achievable. Although seemingly the most difficult, it may be the more feasible approach for genetic conditions such as polycystic kidney disease

This review investigates each option and relates it to the function and the structure of the kidney so as to examine its feasibility and identify the key obstacles to delivery.

Setting the Stage: Normal Kidney Development and Regeneration in Vertebrates

Regenerative biology draws on an understanding of normal developmental processes.

Understanding the molecular basis of kidney development will be the key to the development of regenerative therapies for chronic renal disease.

 

During mammalian development, three separate excretory organs develop: The pronephros, the mesonephros, and the metanephros.

 

 In mammals, it is the paired metanephroi that persist postnatally and constitute the permanent kidney.

 

 

 

The permanent kidney arises via reciprocal interactions between two tissues, the ureteric bud (UB) and the metanephric mesenchyme (MM), the latter arising from the intermediate mesoderm (IM) (1).

 

The UB gives rise to the collecting ducts and the ureter.

 

The MM, which shows much broader potential and gives rise to all other elements of the nephrons, the interstitium, and the vasculature, is regarded as the renal progenitor population (2).

 

 As the UB reaches the MM, signals from the tips of the branching UB induce areas of adjacent MM to aggregate and undergo a mesenchyme-to-epithelial (MET) transition.

 

Each MET event represents the birth of a new nephron with the first nephrons “born” in the center of the MM.

 

The peripheral MM, which has not yet undergone induction, is referred to as the nephrogenic zone.

 

Nephrogenesis in humans is complete by week 36 of gestation (3), whereas it continues for 1 to 2 wk after birth in the mouse and the rat. At that time, it is assumed that the peripheral nephrogenic zone is exhausted.

 

 

 

 

Can the kidney regenerate?

 In simple vertebrates, including fish and amphibians, metanephroi do not form and the permanent excretory unit is the mesonephros. Elasmobranchs (sharks, rays, and skates) constitute a unique example of “kidney” regeneration;

 

their mesonephroi can undergo accelerated nephrogenesis after partial ablation to replace the missing parts (4).

 

In the mammal, partial nephrectomy stimulates hypertrophy of remaining tissue, even in the contralateral kidney, but not the generation of new nephrons (5).

 

However, whereas the resection of an adult kidney does not lead to the regeneration achieved in the liver, the mammalian kidney shares with the majority of organs the ability to repopulate and repair structures that have sustained some degree of injury.

 

This process, termed cellular repair, can be achieved by reentry into mitosis and proliferation of neighboring cells.

 

 

 

 

 

As a result, the kidney can undergo significant remodeling in response to acute damage.

 

For example, obstruction of the ureter can result in the near destruction of the kidney medulla, but once the obstruction is removed, there is a rapid process of reconstruction and repair that will regenerate the tubules of the medulla without forming new nephrons (6).

 

It has been proposed that the cells that elicit such repair come from interstitial cell transdifferentiation (7),

 

 tubular cell dedifferentiation and migration into the areas of damage before redifferentiation (8,9),

 

the recruitment of stem cells from the bone marrow (1014), or the generation of new tubular cells from an endogenous renal stem cell population (reviewed in reference [15]).

 

Which of these is primarily responsible for the cellular repair that is observed after acute damage has not been proved definitively using lineage tracing.

 

However, the mammalian kidney seems to have a very limited potential for structural repairor true regeneration.

 

 

 

While nephrogenesis is occurring in the fetus, there is evidence that a systemic humoral response to nephrectomy allows the enhanced nephrogenesis of the remaining organ (16).

 

 However, nephrogenesis in mammals ceases just before or shortly after birth (3), and the birth of new nephrons has never been reported after this point in time.

 

Chronic injury of the kidney, which is responsible for the majority of cases of end-stage renal failure, results in irreversible glomerular and tubular damage and resultant loss of renal function.

Hence, mammalian kidneys respond to chronic damage by fibrosis, scarring, and irreversible functional loss

Recruitment of Bone Marrow to the Kidney

Can we improve the capacity of the kidney for cellular repair?

 

 The ability of cells that originate from bone marrow to move into distant sites within the body, including the kidney, is now well recognized.

 

 

 

 

 

 

 

 

 

 

 

 Reports have suggested that

 

these cells can transdifferentiate into tubular epithelial cells (12), mesangial cells (11,13,14), glomerular endothelial cells (17,18), and even podocytes (12).

 

 As in most organs, bone marrow–derived cells (BMDC) appear in the kidney in response to damage.

 

The lineage of these cells is unclear, and their ability to elicit transdifferentiation is controversial because the possibility of cell fusion has not always been eliminated (19) (Figure 2).

 

 

 

 

 

The use of lineage tracing has been critical to differentiating these two possibilities. In the case of the muscle, there is evidence from studies in which bone marrow was derived from LysM-Cre mice that it is the monocytic lineage that is recruited and fuses with cells in the target organ (20).

 

This lineage gives rise to the macrophages, which express proteins that are involved in fusion processes.

 

 This does not answer the question of the relative value of this fusion process.

 

 In the brain, BMDC can fuse with Purkinje cells (21), a cell type that is presumed to be unable to divide, possibly leading to a “rejuvenation” of such terminally differentiated cell types. Certainly, the functional outcome of BMDC recruitment must always be assessed.

 

In the context of the kidney, several studies have examined the recruitment of BMDC to kidney in response to damage signals and their transdifferentiative and reparative capacity. The injury models used include ischemia-reperfusion injury (22), folic acid–induced acute tubular injury (23,24), unilateral ureteric obstruction (25), and anti-Thy1 antibody–mediated glomerulonephritis (13).

 

 

 Bone marrow transplantation into HIgA mice, which have glomerulonephritis, improved renal function in these mice (26).

 

 In the studies in which careful quantification of recruitment to the tubular epithelium has been performed, donor-derived bone marrow has contributed between 0.06 and 11% of the epithelial cells (2224).

 

This level does decline with time. An initial recruitment level of 11% dropped to 0.67% at 28 d after ischemia with a concomitant increase in recruitment to the interstitium (22).

 

Two seminal papers in this area (22,23) disagreed on whether there was evidence for transdifferentiation, but both concluded that while BMDC recruitment occurs, repair is predominantly elicited via proliferation of endogenous renal cells. Duffield et al. (23) maintain that BDMC contribute a regenerative cytokine environment that may be important in the resulting functional repair

If this process could be recapitulated pharmacologically, then repair may occur without the need for recruitment.

 

 

 

 

 

Pretreatment of animals with stem cell factor and granulocyte colony-stimulating factor (granulocyte CSF) has been shown to improve recovery from ischemic injury in the absence of transdifferentiation of BMDC (27), and the combined pretreatment with granulocyte CSF and macrophage CSF provides renoprotection from cisplatin-induced renal failure (28). It also may prove valuable to improve recruitment. Held et al. (29) used a genetically induced model of chronic tubular damage that involved hereditary tyrosinemia (mutations in fumarylacetoacetate hydrolase) and mutations in homogentisic acid dioxygenase and reported significant integration (50%) of introduced BMDC.

 

 Hence, a drive for the selection of wild-type cells considerably increases the regeneration process (29). More recently, recruitment and apparent podocytic transdifferentiation of male BMDC to the glomeruli of mice that lacked collagen4α3 has been reported (30).

 

This is a model of Alport syndrome in which there is considerable shedding of protein through the damaged glomerular basement membrane.

 

Whereas podocytes have not been a reported site of bone marrow recruitment in other experimental models,

 

 this study claimed a bone marrow origin for 10% of the podocytes in these mice with a reduction in protein shedding and evidence of collagen replacement within the basement membrane.

 

In this case, access may have been increased as a result of the altered permeability of the basement membrane, but BMDC from mutant mice were not recruited to the glomeruli of mutant recipients, suggesting an active selection for collagen-producing cells.

 

 

 In all of these reports of bone marrow recruitment to damaged kidneys, the lineage of the BMDC that were recruited has not been established. However, adoptive transfer of macrophages into a model of unilateral ureteric obstruction significantly reduced fibrosis in the late stages of this damage state (25).

 

This may have involved transdifferentiation or an altered immunologic response. What also has not been investigated is whether the recruitment of BMDC is good or bad in cases of chronic renal damage

Controlled Dedifferentiation as a Treatment of Renal Disease

Can we repair a kidney by recapitulating development?

Among vertebrates, certain amphibians show a unique ability to regenerate completely complex organs or body parts (31).

 

Salamanders, newts, and axolotls can reconstitute various anatomic structures such as limbs, spinal cord, heart, tail, retina, lens, and upper and lower jaws. In the case of the limb, this process involves dedifferentiation (i.e., loss of a specialized phenotype to return to a progenitor phenotype), proliferation of the resulting primitive blastema, and then redifferentiation of cells in the vicinity of the injury (32) as opposed to the mobilization of a stem cell population per se.

 

Muscle fibers, Schwann cells, periosteal cells, and cells from the connective tissue undergo dedifferentiation and then organize a blastema from which the new limb arises (Figure 3A). Can this be applied in higher vertebrates?

 

Regeneration within the skate mesonephros is a process that takes place in an identified nephrogenic zone using a persistent field of progenitors that can be recruited for regeneration (Figure 3B).

 

Whether these progenitors represent stem cells, as defined as a long-term, self-renewing cell population, has not been established. In mammals, there is no persistent blastema in the adult (Figure 3C).

 

In the absence of such a persistent population of renal progenitors, could such a blastemal field be generated via dedifferentiation in the mammalian kidney?

 

In a recent review of the obstacles to limb regeneration in the mammal (33), it was observed that mammalian limb cells lack the response of reentry into S-phase in response to thrombin (even though this response still would be present if a mouse cell were fused with that of a salamander), and their more complex immune systems respond to damage via the production of fibrosis and the recruitment of inflammatory cells.

 

Possibly as a result of these differences, the production of the blastema that is required for regeneration does not occur, yet there are examples of cell types even in humans that show enormous regenerative capacities, together with more salamander-like properties such as an ability to recommence cell division and dedifferentiate to regenerate.

 

 

 

 

 

 

 

Oligodendrocyte precursor cells have been reverted to multipotential neural stem cells that are able to proliferate and to give rise to neurons, astrocytes, and oligodendrocytes (34).

 

More striking, highly specialized multinucleated muscle cells have been induced to dedifferentiate into mononucleated multipotent progenitor cells that are able to adopt the osteogenic, chondrogenic, adipogenic, and myogenic fates (35).

 

In this case, the dedifferentiation was induced by ectopic expression of the transcriptional repressor Msx1 in combination with growth factor stimulation.

 

Finally, the mouse MRL strain has been shown to have both a marked capacity not to scar and to restore normal myocardial tissue without scarring through a process the authors describe as similar to regeneration in amphibians (36).

 

How feasible is dedifferentiation as a therapy?

 

Postnatal cell turnover in the kidney has never been examined thoroughly, but the cellular complexity of this organ suggests that a dedifferentiation into blastema followed by redifferentiation for the purposes of regeneration would need to be as complex as that seen in the salamander limb.

 

 Hence, we need to understand the blastemal progenitors that give rise to the kidney and to understand the process that long has been observed in the kidney in response to short-term local damage:

 

 

 

 The epithelial-to-mesenchymal transition of tubular cells.

 

If able to be induced, then dedifferentiation might be evoked in situ or ex vivo (Figure 4). In situdedifferentiation would require controllable gene therapy to ensure a cessation of dedifferentiation and subsequent induction of regeneration, or it runs the risk of generating blastemal expansions as for a Wilms’ tumor.

 

 

 

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Dr Iwan Stem cell Therapy Information Center (continiu)

FOUNDER
 
Dr Iwan Suwandy,MHA
 
more info contact
 
iwansuwandy@ gmail.com
 
all free of charge
 
this info to all human in the world
with
 
THE MIGHTY GOD BLESS
 
 
PHYSIOLOGY  and  PATOPHISIOLOGY OF THE STEM CELL
 
 
 

STEM CELL PHYSIOLOGY

There are many cell of blood and immune body are continuously produced throughout life from hemopoietic stem cells residing in the bone marrow.

The ability of these cells to perform this function is why bone-marrow transplants can be used to treat leukemia and other blood or immune disorders.

Researchers in the Stem Cell Physiology Research Unit, located at The Biomedical Research Centre at UBC, are studying the biology of bone marrow stem cells and the immune system.

They are focusing on understanding the molecular mechanisms that control how bone-marrow stem cells self-renew and how they differentiate into and function as specific types of blood cells.

Their long-term goal is to understand how defence, repair, and regeneration are regulated and how this knowledge can be exploited to benefit health and offer new treatments for disease.

The Biomedical Research Centre’s researchers recently made important discoveries about the ways bone marrow stem cells differentiate into various types of cells that can fuse with cells in other tissues – such as brain or muscle – to contribute genes.

EAD MORE INFO

ABOUT BONE MARROW  STEM CELL

Mesenchymal stem cells: the ‘other’ bone marrow stem cells

Last updated: 

20 Jun 2012

Mesenchymal stem cells: the 'other' bone marrow stem cells

Mesenchymal stem cells (MSCs) can make several types of cells belonging to our skeletal tissues, such as cartilage, bone and fat. Scientists are investigating how MSCs might be used to treat bone and cartilage diseases. Some MSC research is also exploring therapies for other diseases, but the scientific basis for these applications has not yet been established or widely accepted.

Did you know?

Mesenchymal stem cells make up about 0.001-0.01% of all the cells in your bone marrow

Human mesenchymal stem cells grown in a single layer on the bottom of a flask; 4x magnificationHuman mesenchymal stem cells grown in a single layer on the bottom of a flask; 4x magnification 

Human mesenchymal stem cells grown in a single layer on the bottom of a flask; 10x magnificationHuman mesenchymal stem cells grown in a single layer on the bottom of a flask; 10x magnification 

Bone cells made from MSCs; the colour is from a stain used to mark the bone cells (von Kossa stain) Bone cells made from MSCs; the colour is from a stain used to mark the bone cells (von Kossa stain) 

Fat cells made from MSCs; the colour is from a stain called Nile red O that marks fat cells red Fat cells made from MSCs; the colour is from a stain called Nile red O that marks fat cells red 

Cartilage cells made from MSCs; cartilage cells are stained red using the dye Safranin O Cartilage cells made from MSCs; cartilage cells are stained red using the dye Safranin O 

Cartilage cells made from MSCs; the cartilage cells are marked brown by a process called immunostainingCartilage cells made from MSCs; the cartilage cells are marked brown by a process called immunostaining 

What can mesenchymal stem cells do?

Mesenchymal stem cells (MSCs) are an example of tissue or ‘adult’ stem cells. They are ‘multipotent’, meaning they can produce more than one type of specialized cell of the body, but not all types. MSCs make the different specialized cells found in the skeletal tissues. For example, they can differentiate − or specialize  −  into cartilage cells (chondrocytes), bone cells (osteoblasts) and fat cells (adipocytes). These specialized cells each have their own characteristic shapes, structures and functions, and each belongs in a particular tissue.

Some early research suggested that MSCs might also differentiate into many different types of cells that do not belong to the skeletal tissues, such as nerve cells, heart muscle cells, liver cells and endothelial cells, which form the inner layer of blood vessels. These results have not been confirmed to date. In some cases, it appears that the MSCs fused together with existing specialized cells, leading to false conclusions about the ability of MSCs to produce certain cell types. In other cases, the results were an artificial effect caused by chemicals used to grow the cells in the lab.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

Where are mesenchymal stem cells found?

MSCs were originally found in the bone marrow. There have since been many claims that they also exist in a wide variety of other tissues, such as umbilical cord blood, adipose (fat) tissue and muscle. It has not yet been established whether the cells taken from these other tissues are really the same as, or similar to, the mesenchymal stem cells of the bone marrow.

The bone marrow contains many different types of cells. Among them are blood stem cells (also called hematopoietic stem cells; HSCs) and a variety of different types of cells belonging to a group called ‘mesenchymal’ cells. Only about 0.001-0.01% of the cells in the bone marrow are mesenchymal stem cells.

It is fairly easy to obtain a mixture of different mesenchymal cell types from adult bone marrow for research. But isolating the tiny fraction of cells that are mesenchymal stem cells is more complicated. Some of the cells in the mixture may be able to form bone or fat tissues, for example, but still do not have all the properties of mesenchymal stem cells. The challenge is to identify and pick out the cells that can both self-renew (produce more of themselves) and can differentiate into three cell types – bone, cartilage and fat. Scientists have not yet reached a consensus about the best way to do this.

Developing new treatments using mesenchymal stem cells

No treatments using MSCs are yet available. However, several possibilities for their use in the clinic are currently being explored.

AFTER STUDY THE PHYSIOLOGY,HISTOLOGY AND PATOPHYSIOLOGY OF CELL

AND STEM CELL, I HAVE MADE CONCLUSION THE ONLY WAYTO REPAIR THE

DIABETIC NEPHRPTAHY ARE

THE STEM CELL THERAPY

LET’S WE STUDYTHE THE DIABETIC NEPHROPATHY STEM CELL THERAPY AROUND THE WORLD

 

Driwan Stem Cell Therapy Infprmation Center(continiu)

FOUNDER
 
Dr Iwan Suwandy,MHA
 
more info contact
 
iwansuwandy@ gmail.com
 
all free of charge
 
this info to all human in the world
with
 
THE MIGHTY GOD BLESS
 
 
PHYSIOLOGY  and  PATOPHISIOLOGY OF THE STEM CELL
 
 
 

STEM CELL PHYSIOLOGY

There are many cell of blood and immune body are continuously produced throughout life from hemopoietic stem cells residing in the bone marrow.

The ability of these cells to perform this function is why bone-marrow transplants can be used to treat leukemia and other blood or immune disorders.

Researchers in the Stem Cell Physiology Research Unit, located at The Biomedical Research Centre at UBC, are studying the biology of bone marrow stem cells and the immune system.

They are focusing on understanding the molecular mechanisms that control how bone-marrow stem cells self-renew and how they differentiate into and function as specific types of blood cells.

Their long-term goal is to understand how defence, repair, and regeneration are regulated and how this knowledge can be exploited to benefit health and offer new treatments for disease.

The Biomedical Research Centre’s researchers recently made important discoveries about the ways bone marrow stem cells differentiate into various types of cells that can fuse with cells in other tissues – such as brain or muscle – to contribute genes.

EAD MORE INFO

ABOUT BONE MARROW  STEM CELL

Mesenchymal stem cells: the ‘other’ bone marrow stem cells

Last updated: 

20 Jun 2012

Mesenchymal stem cells: the 'other' bone marrow stem cells

Mesenchymal stem cells (MSCs) can make several types of cells belonging to our skeletal tissues, such as cartilage, bone and fat. Scientists are investigating how MSCs might be used to treat bone and cartilage diseases. Some MSC research is also exploring therapies for other diseases, but the scientific basis for these applications has not yet been established or widely accepted.

Did you know?

Mesenchymal stem cells make up about 0.001-0.01% of all the cells in your bone marrow

Human mesenchymal stem cells grown in a single layer on the bottom of a flask; 4x magnificationHuman mesenchymal stem cells grown in a single layer on the bottom of a flask; 4x magnification

Human mesenchymal stem cells grown in a single layer on the bottom of a flask; 10x magnificationHuman mesenchymal stem cells grown in a single layer on the bottom of a flask; 10x magnification

Bone cells made from MSCs; the colour is from a stain used to mark the bone cells (von Kossa stain) Bone cells made from MSCs; the colour is from a stain used to mark the bone cells (von Kossa stain)

Fat cells made from MSCs; the colour is from a stain called Nile red O that marks fat cells red Fat cells made from MSCs; the colour is from a stain called Nile red O that marks fat cells red

Cartilage cells made from MSCs; cartilage cells are stained red using the dye Safranin O Cartilage cells made from MSCs; cartilage cells are stained red using the dye Safranin O

Cartilage cells made from MSCs; the cartilage cells are marked brown by a process called immunostainingCartilage cells made from MSCs; the cartilage cells are marked brown by a process called immunostaining

What can mesenchymal stem cells do?

Mesenchymal stem cells (MSCs) are an example of tissue or ‘adult’ stem cells. They are ‘multipotent’, meaning they can produce more than one type of specialized cell of the body, but not all types. MSCs make the different specialized cells found in the skeletal tissues. For example, they can differentiate − or specialize  −  into cartilage cells (chondrocytes), bone cells (osteoblasts) and fat cells (adipocytes). These specialized cells each have their own characteristic shapes, structures and functions, and each belongs in a particular tissue.

Some early research suggested that MSCs might also differentiate into many different types of cells that do not belong to the skeletal tissues, such as nerve cells, heart muscle cells, liver cells and endothelial cells, which form the inner layer of blood vessels. These results have not been confirmed to date. In some cases, it appears that the MSCs fused together with existing specialized cells, leading to false conclusions about the ability of MSCs to produce certain cell types. In other cases, the results were an artificial effect caused by chemicals used to grow the cells in the lab.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

Where are mesenchymal stem cells found?

MSCs were originally found in the bone marrow. There have since been many claims that they also exist in a wide variety of other tissues, such as umbilical cord blood, adipose (fat) tissue and muscle. It has not yet been established whether the cells taken from these other tissues are really the same as, or similar to, the mesenchymal stem cells of the bone marrow.

The bone marrow contains many different types of cells. Among them are blood stem cells (also called hematopoietic stem cells; HSCs) and a variety of different types of cells belonging to a group called ‘mesenchymal’ cells. Only about 0.001-0.01% of the cells in the bone marrow are mesenchymal stem cells.

It is fairly easy to obtain a mixture of different mesenchymal cell types from adult bone marrow for research. But isolating the tiny fraction of cells that are mesenchymal stem cells is more complicated. Some of the cells in the mixture may be able to form bone or fat tissues, for example, but still do not have all the properties of mesenchymal stem cells. The challenge is to identify and pick out the cells that can both self-renew (produce more of themselves) and can differentiate into three cell types – bone, cartilage and fat. Scientists have not yet reached a consensus about the best way to do this.

Developing new treatments using mesenchymal stem cells

No treatments using MSCs are yet available. However, several possibilities for their use in the clinic are currently being explored.

Bone and cartilage repair
The ability of MSCs to differentiate into bone cells called osteoblasts has led to their use in early clinical trials investigating the safety of potential bone repair methods. These studies are looking at possible treatments for localized skeletal defects (damage at a particular place in the bone).

Other research is focussed on using MSCs to repair cartilage. Cartilage covers the ends of bones and allows one bone to slide over another at the joints. It can be damaged by a sudden injury like a fall, or over a long period by a condition like osteoarthritis, a very painful disease of the joints. Cartilage does not repair itself well after damage. The best treatment available for severe cartilage damage is surgery to replace the damaged joint with an artificial one. Because MSCs can differentiate into cartilage cells called chondrocytes, scientists hope MSCs could be injected into patients to repair and maintain the cartilage in their joints. Researchers are also investigating the possibility that transplanted MSCs may release substances that will tell the patient’s own cells to repair the damage.

Many hurdles remain before this kind of treatment can become a reality. For example, when MSCs are transplanted, most of them are rapidly removed from the body. Researchers are working on new techniques for transplanting the cells, such as developing three-dimensional structures or scaffolds that mimic the conditions in the part of the body where the cells are needed. These scaffolds will hold the cells and encourage them to differentiate into the desired cell type.

Heart and blood vessel repair
Some studies in mice suggest that MSCs can promote formation of new blood vessels in a process called neovascularisation. MSCs do not make new blood vessel cells themselves, but they may help with neovascularisation in a number of ways. For example, they may release proteins that stimulate the growth of other cells called endothelial precursors – cells that will develop to form the inner layer of blood vessels. Such studies on animals have led researchers to hope that MSCs may provide a way to repair the blood vessel damage linked to heart attacks or diseases such as critical limb ischaemia. A number of early stage clinical trials using MSCs in patients are currently underway but it is not yet clear whether the treatments will be effective.

Inflammatory and autoimmune diseases
Several claims have been made that MSCs are able to avoid detection by the immune system and can be transplanted from one patient to another without risk of immune rejection by the body. However, these claims have not been confirmed by other studies. It has also been suggested that MSCs may be able to slow down the multiplication of immune cells in the body to reduce inflammation and help treat transplant rejection or autoimmune diseases. Again, this has yet to be proven and much more evidence is needed to establish whether MSCs could really be used for this kind of application.

Current research and the future

Research into therapies using MSCs is still in its infancy. A great deal more work is needed before such therapies can be used routinely in patients. Questions remain about how the cells can be controlled, how they will behave when transplanted into the body, how they can be delivered to the right place so that they work effectively and so forth. By studying how these cells work and interact within the body, researchers hope to develop safe and effective new treatments in the future..

source

Primary Investigator: 
 
 

Stem Cell Physiology and Pathophysiology

 Diabetes  and Hemopoetic Stem Cell
 
Why Diates impairs the interactions between long-term hematopoietic stem cells ?
to answer this question pleae read carefulyy the abstrct of this reseach

Diabetes impairs the interactions between long-term hematopoietic stem cells and osteopontin-positive cells in the endosteal niche of mouse bone marrow.

Abstract

Hematopoietic stem cells (HSCs) are maintained, and their division/proliferation and quiescence are regulated in the microenvironments, niches, in the bone marrow.

Although diabetes is known to induce abnormalities in HSC mobilization and proliferation through chemokine and chemokine receptors, little is known about the interaction between long-term

HSCs (LT-HSCs)

and

osteopontin-positive (OPN) cells

in

endosteal niche.

To examine this interaction, LT-HSCs and OPN cells were isolated from streptozotocin-induced diabetic and nondiabetic mice.

In diabetic mice, we observed a reduction in the number of LT-HSCs and OPN cells and impaired expression of Tie2, β-catenin, and N-cadherin on LT-HSCs and β1-integrin, β-catenin, angiopoietin-1, and CXCL12 on OPN cells.

In an in vitro coculture system,

LT-HSCs isolated from nondiabetic mice exposed to diabetic OPN cells showed abnormal mRNA expression levels of Tie2 and N-cadherin. Conversely,

in LT-HSCs derived from diabetic mice exposed to nondiabetic OPN cells, the decreased mRNA expressions of Tie2, β-catenin, and N-cadherin were restored to normal levels.

The effects of diabetic or nondiabetic OPN cells on LT-HSCs shown in this coculture system were confirmed by the coinjection of LT-HSCs and OPN cells into bone marrow of irradiated nondiabetic mice.

Our results

provide new insight into

the treatment of

diabetes-induced LT-HSC abnormalities

and suggest that

the replacement of OPN cells may represent a novel treatment strategy.

to understan this situation we must understand

the physiology of normal cell

Overview

  • The typical cell comprises a nucleus and cytoplasm, separated by the nuclear membrane
  • The cytoplasm is separated from interstitial fluid by the cell membrane
  • The different substances making up a cell are termed its “protoplasm” and include:
    • water (usually 70%-85%)
    • electrolytes – chiefly potassium, magnesium, phosphate, sulphate, bicarbonate, and a little sodium, chloride and calcium
    • proteins (usually 10%-20%) – structural and globular, including enzymes
    • lipids (usually 2%) – particularly phospholipids, cholesterol, triglycerides, neutral fats
    • carbohydrates (usually 1%) – usually as glycogen
  • The cell and its organelles are surround by membranes composed of lipids and proteins
    • these include the cell membrane, nuclear membrane, and membranes of the ER, mitochondria, lysosomes and Golgi apparatus
    • each prevents free movement of water and water-soluble substances between cell compartments
  • The cell membrane is a lipid bilayer with inserted proteins
    • the lipid bilayer is mostly phospholipids and cholesterol
    • it is permeable to lipid-soluble substances, but is a major barrier to water-soluble substances such as ions
    • integral proteins protrude through the membrane, while peripheral proteins are attached to the inner surface
    • many integral proteins form structural channels, or carrier proteins
    • peripheral proteins are usually enzymes
    • the membrane is studded with glycoproteins, which are thought to repel other negatively charged molecules, allow attachment to some other cells and act as receptors for binding hormone
  • The ER synthesizes substances in the cell
    • aided by a large surface area
    • materials made include proteins, carbohydrates, lipids, lysosomes, peroxisomes, and secretory granules
    • lipids are made within the ER wall
    • proteins are made by mRNA attaching to ribosomes on the outer surface of the ER
  • The Golgi apparatus is prominent in secretory cells
    • synthesis of lysosomes, secretory vesicles and other cytoplasmic inclusions
    • transport vesicles are pinched-off bits of ER which then fuse with the Golgi apparatus
  • Lysosomes provide the cell with a digestive system
    • small round vesicles containing digestive enzymes
    • usually cordoned-off by a non-reactive membrane
  • Mitochondria release energy in the cell
    • via the citric acid cycle and oxidative enzymes, producing ATP
    • self-replicative and almost certainly originally symbiotic
  • The nucleus acts as a control centre of the cell and contains large amounts of DNA
    • separated from the cytoplasm by a nuclear envelope, pierced by several thousand pores
    • most also contain one or more nucleoli, which do not have membranes; these contain large amounts of RNA, and are enlarged in cells actively synthesizing proteins

Ingestion by the Cell – Endocytosis

  • Small particles enter the cell through diffusion or active transport. Very large particles enter by endocytosis, either pinocytosis or phagocytosis
  • Pinocytosis is the ingestion of small globules of extracellular fluid, forming minute vesicles in the cytoplasm
  • Phagocytosis is the ingestion of large particles such as bacteria, cells, and bits of degenerating tissue
  • Substances so absorbed are digested in the cell by lysosomes. The products of digestion are small amino acids, lipids, glucose, phosphate

Synthesis of Cellular Structures

  • The synthesis of most structures begins in the ER. The rough ER is so named because large numbers of ribosomes attach to the outer surface. Small ER vesicles continually break off from the smooth ER and migrate to the Golgi apparatus.

Extraction of Energy by Mitochondria

  • Almost all oxidative reactions occur inside mitochondria and the energy released is in the form of ATP. ATP has two very labile high-energy phosphate bonds (12,000 calories per mole)
  • Most of the ATP produced in cells is made by mitochondria. About 5% is made by glycolysis, the rest by the citric acid cycle. The process is called the “chemosmotic mechanism”
  • ATP is used for many cellular functions, particularly membrane transport (Na-K-ATPase), synthesis of chemical compounds, and mechanical work

Locomotion and Ciliary Movements by Cells

  • Amoeboid locomotion is the movement of an entire cell in relation to its surroundings (eg. a white blood cell through tissues). It begins with protrusion of a pseudopodium from one end of the cell, with continual exocytosis, and continual endocytosis of the membrane at the mid and rear portions of the cell.
  • Two effects are essential to forward movement: attachment of the pseudopodium, and adequate energy for the movement. In the cytoplasm are molecules of the protein actin, which polymerize to form a filamentous network that contracts on binding to another protein such as myosin.
  • Amoeboid movement is initiated usually by a chemotactic factor. The process is called chemotaxis.
  • Ciliary movement is a whip-like movement of cilia on the surface of cells (only in the respiratory tract, and in the uterine tubules). The mechanism is not known.

Genetic Control of Cell Function

  • Cell genes control protein synthesis. Each gene is a double-stranded helical molecule of DNA that controls the formation of RNA. RNA spreads through the cell to control the formation of a specific protein.
  • Nucleotides are organized to form two strands of DNA bound loosely to each other. There are three building blocks: phosphoric acid, deoxyribose (a sugar), and four nitrogenous bases (two purines: adenine and guanine; two pyrimidines, thymine and cytosine). Adenine always bonds with thymine, and guanine always bonds with cytosine.
  • The genetic code consists of triplets of bases. Each is called a code word. These determine the sequence of amino acids added to the protein.
  • DNA code is transferred to RNA code by the process of transcription. It occurs in the nucleus, where each DNA code word forms a complementary RNA triplet called a codon. The basic building blocks are almost the same except ribose replaces deoxyribose, and uracil replaces thymine.
  • The next step is the activation of the nucleotide, with the addition of two phosphate radicals derived from ATP. It makes available large amounts of energy to promote the reactions that add each new RNA nucleotide to the end of the RNA chain.
  • The DNA strand is used as a template to assemble the RNA molecule from activated nucleotides, under the influence of the enzyme RNA polymerase.
  • There are three different types of RNA:
    • mRNA, carries the genetic code to the cytoplasm to control the formation of proteins
    • rRNA, which along with proteins forms the ribosomes, the molecules in which proteins are actually assembled
    • tRNA, which transports activated amino acids to the ribosomes – 20 types for 20 amino acids
  • The operons of the DNA strand control biochemical synthesis and are activated by the promoter. The operon is controlled by a repressor and an activator operator, and through negative feedback by the cell product. I have no idea what this paragraph means.

The DNA Genetic System

  • With the exception of some very long-lived cells (eg. nerve cells), most cells need to be able to reproduce their own cell type.
  • Reproduction begins with replication of the DNA. As they are replicated, the DNA strands are repaired and proofread. Mistakes (mutations) rarely escape enzymes that cut out defective bits and replace them with appropriate complementary nucleotides.
  • Entire chromosomes (46, 23 pairs) are replicated. In addition to the DNA, there is a fair bit of protein as histones, molecules around which the DNA is coiled to pack it in. The two newly-formed chromosomes remain temporarily attached to each other at a point called the centromere, near the centre. The duplicated but still-attached chromosomes are called chromatids.

Mitosis

  • This is the process by which the cell splits into two new daughter cells.
  • Two pairs of centrioles, small structures close to one pole of the nucleus, begin to move apart. Microtubules grow radially away from each of the centriole pairs, forming a spiny star called the aster at each end of the cell. The complex of microtubules between the pairs is called the spindle, and the entire set of microtubules plus the pairs of centrioles the mitotic apparatus.
  • Prophase is the beginning of mitosis – while the spindle is forming, the chromosomes become condensed into defined chromosomes
  • Prometaphase is the stage at which microtubular spines puncture and fragment the nuclear envelope, and microtubules become attached to the chromatids at the centromere
  • Metaphase is the stage at which the two asters are pushed farther and farther apart
  • Anaphase is the stage at which the two chromatids of each chromosome are pulled apart at the centromere. All 46 pairs are separated, forming two sets of 46 daughter chromosomes.
  • Telophase is the stage at which the two sets of daughter chromosomes are pulled completely apart. Then the mitotic apparatus dissolves and a new nuclear membrane develops around each set of chromosomes.

MYELIN CELL

MYELIN AXON

Pada sel saraf

selubung Mielin 

Neuron-no labels.png

adalah lapisan fosfolipid 

yang membungkus akson secara konsentrik. 

MYELIN SHEATH

(SELUBUNG MYELIN)

Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork

  • Shweta Aggarwal,
     
  • Nicolas Snaidero,
     
  • Gesa Pähler,
     
  • Steffen Frey,
     
  • Paula Sánchez,
     
  • Markus Zweckstetter,
     
  • Andreas Janshoff,
     
  • Anja Schneider,
     
  • Marie-Theres Weil,
     
  • Iwan A. T. Schaap,
     
  • Dirk Görlich,
     
  • Mikael Simons

Abstract

Rapid conduction of nerve impulses requires coating of axons by myelin. To function as an electrical insulator, myelin is generated as a tightly packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern myelin membrane biogenesis is required to understand myelin disassembly as it occurs in diseases such as multiple sclerosis. Here, we show that myelin basic protein drives myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in myelin membrane biogenesis with implications for disabling demyelinating diseases of the central nervous system.

Author Summary

Myelin is a specialized membrane that covers axons and serves as an insulator to enable the fast conduction of the action potentials.

The importance of myelin membrane is highlighted in demyelinating diseases such as multiple sclerosis, which lead to severe neurological disability.

Here, we describe a physicochemical mechanism of how myelin is generated and assembled.

We find that myelin basic protein (MBP) molecules undergo a phase transition into a cohesive meshwork at the membrane interface, which drives structural changes in the membranes.

We provide evidence that the interaction of myelin basic proteins with the inner leaflet of the myelin bilayer results in charge neutralization and triggers self-association of the protein into larger polymers.

Interactions between MBP molecules are mediated by hydrophobic phenylalanine residues and amyloid-like association.

We propose that phase transition of MBP from a cytoplasmic soluble pool into a cohesive functional amyloid-like assembly is one of the key mechanisms in myelin membrane biogenesis

Sel Schwann

merupakan sel yang membentuk selubung

pada sistem saraf tepi,

sedangkan oligodendrosit merupakan sel yang membentuk selubung yang sama pada sistem saraf pusat.

Selubung mielin merupakan karakteristik dari vertebrata (gnathostome), tetapi juga diangkat oleh evolusi pararel beberapa invertebrata.[1] 

Mielin ditemukan oleh Louis-Antoine Ranvier pada tahun 1878.

SCHWAN CELL

LT-HSCs derived from diabetic


Cellular Injury and Adaptation

Overview

  • Tissue injury starts with molecular or structural damage to cells. When faced with injury, cells can either adapt, sustain reversible injury, or die. Cellular adaptation occurs when stressors result in a new but altered state that preserves viability of the cell (eg. hypertrophy, atrophy)
  • There are two morphologic patterns of cell death: apoptosis and necrosis
    • apoptosis is characterized by chromatin condensation and fragmentation, occurs singly or in small clusters only, and results in the elimination of unwanted cells during embryogenesis and some physiologic and pathologic states
    • necrosis is characterized by swelling, denaturation of proteins, breakdown of cellular organelles, and cell rupture

Causes of Cellular Injury

  • Hypoxia
    • ischaemia (loss of supply)
    • inadequate oxygenation (respiratory failure)
    • loss of oxygen-carrying capacity of the blood (anaemia, CO poisoning)
  • Physical agents
    • trauma
    • thermal insult
    • radiation
    • electric shock
  • Chemical agents and drugs
    • therapeutics
    • non-therapeutic agents
  • Infectious agents
    • viruses
    • rickettsiae
    • bacteria
    • fungi
    • parasites
  • Immunologic reactions
  • Genetic derangements
  • Nutritional imbalances

General Mechanisms of Cell Injury

  • Oxygen-derived free radicals are produced in many conditions and cause damage to cell structure and function
  • Loss of calcium homeostasis, with increased intracellular calcium – this activates phospholipases, proteases, ATPases and endonucleases
  • ATP depletion
  • Defects in membrane permeability

Ischaemic and Hypoxic Injury

  • The key is early loss of oxidative phosphorylation and ATP generation by mitochondria
  • Decreased ATP stimulates aerobic glycolysis; glycogen is quickly depleted and lactate and inorganic phosphate produced, dropping intracellular pH
  • Manifests histologically as swelling, from:
    • loss of Na-K-ATPase, causing sodium to enter the cell, potassium to leave, and an osmotic gain of water
    • increased intracellular osmotic load from the accumulation of lactate and inorganic phosphate
    • polarized membranes lose their polarity
  • All of these are reversible if oxygenation is restored
  • The sentinel event for irreversible injury seems to be damage to membranes
  • Calcium is probably the most important mediator of biochemical and morphologic alterations leading to cell death
  • Reperfusion injury
    • mechanism is not well understood, but clinically important particularly to myocardial and cerebral infarction
    • definition would be a loss of cells in addition to those irreversibly damaged, by restoration of oxygenation at the end of an ischaemic episode
    • bathing compromised cells in high concentrations of calcium when they can’t fully regulate their internal ionic environment?
    • local recruitment of inflammatory cells, releasing reactive species?
    • incomplete oxygen reduction by damaged mitochondria yielding reactive species?

Free Radical-Induced Injury

  • Free radicals are reactive, unstable species that interact with proteins, lipids and carbohydrates. They are created by absorption of radiant energy, oxidative metabolism, or enzymatic conversion of exogenous chemicals.
  • Important free radicals are superoxide (from oxygen), hydrogen peroxide, hydroxyls and nitric oxide.
  • They damage cells through peroxidation of lipids, cross-linking of proteins by forming disulfide bonds, inactivation of sulfhydryl enzymes, and induction of direct DNA damage
  • Free radical termination is by antioxidants (vitamin E, glutathione, ceruloplasmin, transferrin), or enzymes (superoxide dismutase, catalase, glutathione peroxidase)

Chemical Injury

  • Direct injury. Mercury is a good example, binding to sulfhydryl groups of cell membrane proteins, increasing permeability and inhibiting ATPase-dependent transport.
  • Indirect injury. Conversion to toxic metabolites (carbon tetrachloride).

 Abnormal cell injury in diabetic

Abnormal Cell Injury In Dibetes

Myelin splitting,

Schwann cell injury

and demyelination

in feline diabetic neuropathy

source

Abstract

Nerve biopsy samples from two cats with spontaneously occurring diabetes were examined.

The predominant nerve fiber abnormalities observed were restricted to the myelin sheath and Schwann cell.

Reactive, degenerative and proliferative Schwann cell changes were evident but the most striking abnormality encountered was splitting and ballooning of the myelin sheath.

These observations highlight

the significance of Schwann cell injury in the pathogenesis of diabetic neuropathy

THE PATHOGENESIS OF THE LATE COMPLICATIONS OF DIABETES MELLITUS.

Dr Angela Barbour. Discipline of Pathology

University of Adelaide

2009

This material has been reproduced and communicated to you by or on behalf of Adelaide University pursuant to Part

VB of the Copyright Act 1968 (the Act).

COMPLICATIONS OF DIABETES MELLITUS

 

Vascular

 

 

Large arteries (macroangiopathy): atherosclerosis and related complications

 

 

Arterioles: hyaline arteriolosclerosis

 

 

Microangiopathy/microvascular: capillary basement membrane thickening

 

 

Renal

 

 

Diabetic nephropathy

 

 

Osteoblasts and Bone Marrow Mesenchymal Stromal Cells Control Hematopoietic Stem Cell Migration and Proliferation in 3D In Vitro Model

  • Ana Paula D. N. de Barros,
     
  • Christina M. Takiya,
     
  • Luciana R. Garzoni,
     
  • Mona Lisa Leal-Ferreira,
     
  • Hélio S. Dutra,
     
  • Luciana B. Chiarini,
     
  • Maria Nazareth Meirelles,
     
  • Radovan Borojevic,
     
  • Maria Isabel D. Rossi

Abstract

Background

Migration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow–derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs.

Methodology/Principal Findings

A complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34+ cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34+ cells was decreased.

Conclusions/Significance

Undifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation.

Infection -> acute and chronic pyelonephritis

 

 

Atherosclerosis related including infarction and renal artery stenosis

 

 

Ocular

 

 

Cataracts

 

 

Glaucoma

 

 

Diabetic retinopathy

 

 

Non-proliferative

 

 

Proliferative

 

 

Macular oedema

 

 

Neuropathy

 

 

Peripheral nerves

 

 

Autonomic nerves

 

 

Mononeuropathy

 

 

Diabetic polyradiculopathy

 

 

Skin

 

 

Ulcers: multifactorial

 

 

Impaired sensation due to neuropathy

 

 

Predisposition to infection

 

 

Impaired blood supply due to atherosclerosis and microangiopathy impairing healing

 

 

Necrobiosis lipoidica diabeticorum (rare)

 

 

Infection

 

 

Predisposition to infection (e.g. pulmonary, urinary tract, skin) related to hyperglycaemia and impaired function of

phagocytes and other inflammatory cells

 

 

 

Liver: non-alcoholic steatosis, steatohepatitis and cirrhosis

 

 

Acute metabolic complications

 

 

Diabetic ketoacidosis (primarily in type 1)

 

 

Non-ketotic hyperosmolar coma (type 2)

 

 

Hypoglycaemia from too much insulin or hypoglycaemics

 

Nephropathy, atherosclerosis, neuropathy, ocular complications

 

Are late complications

 

 

Risk increases in relation to duration of hyperglycaemia

 

 

Usually become apparent in 2nd decade of hyperglycaemia, may be present at time of diagnosis of type 2 which often

has a long asymptomatic period

 

 

 

Better blood glucose control reduces risk

 

 

Other undefined factors modulate the risk e.g. genetic

 

 

Nephropathy, neuropathy, retinopathy are largely related to microangiopathy

 

BACKGROUND HISTOLOGY

Connective tissue

 

Cells include: fibroblasts, myofibroblasts, mast cells, adipocytes, macrophages, undifferentiated mesenchymal cells

 

 

Extracellular matrix

 

 

Fibres

 

 

Collagen, including reticulin

 

 

Elastin

 

 

Ground substance: Glycosaminoglycans bound to proteoglycans

 

 

Structural glycoproteins e.g. laminin, fibrillin

 

 

Tissue fluid

Connective tissue proper: loose and dense

 

Specialised connective tissue e.g. adipose tissue, bone, cartilage

 

 

Basement membranes (BM)

 

Epithelial, endothelial and mesothelial cells sit on a BM

 

 

Similar material surrounds Schwann cells and various other connective tissue cells (e.g. adipocytes, smooth muscle

cells) – termed basal lamina

 

 

 

Composition

 

 

Specialised extracellular matrix

 

 

Central electron dense layer (lamina densa) with less distinct electron lucent layers (lamina rara) on either side (all

3 together sometimes termed basal lamina)

 

 

 

Delicate network of predominantly type IV collagen in a matrix of glycoproteins (e.g. laminin) and other

extracellular components (e.g. heparan sulphate proteoglycan) largely produced by the overlying cells

 

 

 

+/- reticular layer: collagen type III originating from underlying connective tissue cells

 

 

Often too thin to be seen distinctly on H&E with light microscopy except in areas where it is thicker (e.g. trachea)

but can be seen with special stains on light microscopy

 

 

 

Function

 

 

Bonds cells to underlying connective tissue

 

 

Provides framework for cell development and regeneration

 

 

Freely permeable to small molecules but impedes passage of macromolecules

 

Arteries

Layers (general):

 

Intima: endothelium (simple squamous), basement membrane, (+ small amount of connective tissue/elastin in some),

internal elastic lamina (except in smallest arterioles)

 

 

 

Media: variable amounts of smooth muscle and extracellular matrix, predominantly elastin; in some vessels an external

elastic lamina is also present

 

 

 

Adventitia: connective tissue including abundant elastin, vasa vasorum in larger vessels

Media

 

 

 

Large arteries (aorta and it’s main branches): abundant elastic tissue

 

 

Medium (distributing arteries) and small (<2mm) arteries: predominantly smooth muscle

 

 

Arterioles (diam 100um or less): several layers of smooth muscle cells only

Smooth muscle cells produce the extracellular matrix including elastin

 

 

PROPOSED GENERAL MECHANISMS UNDERLYING CHRONIC COMPLICATIONS IN DIABETES:

Complex and not fully understood, different pathways that interact. Genetic factors in the patient also have an important

influence.

 

Hyperglycaemia ->

 

 

Formation of advanced glycation end products (AGE) – glucose binds irreversibly to protein amino groups. AGE may

also form on lipids, nucleic acids.

 

 

 

AGE modified extracellular matrix components

 

 

Lead to protein cross-linking

 

 

Are resistant to proteolytic digestion

 

 

Trap other proteins (e.g. plasma proteins)

 

 

May promote cell damage

 

 

Non-enzymatic glycation of haemoglobin: HbA1c – serves as marker of glycemic control

 

 

May alter intracellular signalling, gene expression and oxygen derived free radical formation

 

 

Increase in aldose reductase pathway

 

 

In cells not requiring insulin for glucose uptake e.g. Schwann cells, retinal pericytes, lens of eye

 

 

Metabolism of excess intracellular glucose -> excessive glucose metabolites (e.g. sorbitol) with reduced synthesis of

an important antioxidant -> osmotic cell injury and increased susceptibility to oxidative injury

 

 

 

Production of reactive oxygen species ->

 

 

Upregulation of growth factor expression e.g. VEGF

 

 

Alteration of proteins and lipoproteins

 

 

Cell damage

 

 

Increased activation of protein kinase C (PKC) signal transduction pathway

 

 

May be related to AGE formation

 

 

Activation of signal transduction pathways for extracellular matrix protein production

 

 

Overactive renin-angiotensin system

 

 

Angiotensin II stimulates production of important growth factors e.g. TGF-beta that plays a role in extracellular

matrix formation in the renal mesangium and VEGF is important in proliferative retinopathy

 

 

 

Important in nephropathy and retinopathy

Understanding pathogenesis helps in the development of potential treatments e.g. use of inhibitors of AGE formation,

 

antioxidants, angiotensin II inhibitors

 

The simplified version

 

 

 

Increased amounts of extracellular matrix with altered structure and function due to:

 

 

Upregulation (various mechanisms) of production of various growth factors and cytokines -> increased extracellular

matrix production

 

 

 

AGE modified extracellular matrix proteins -> cross-linking, plasma protein trapping, reduced proteolytic digestion

 

 

Cell damage e.g. via aldose reductase pathway and osmotic injury, activation of reactive oxygen species

The microangiopathy (capillary basement membrane thickening), hyaline arteriolar changes and mesangial thickening in

 

diabetes are caused by the above processes. Hypertension may play a role in the development of hyaline arteriolosclerosis.

 

 

Normal renal glomerular structure

 

Filtration barrier

 

 

Endothelial cells, epithelial cells and basement membrane

 

 

Endothelium

 

 

Fenestrated with large pores that only prevent blood cells and platelets from passing through

 

 

The diaphragm that typically spans fenestrations between endothelial cells in certain other vascular beds is absent

 

 

Epithelial cells (podocytes)

 

 

Extensive array of processes that interdigitate on outside of capillary with slit like spaces (filtration slits) between

 

 

Each filtration slit is spanned by a thin filtration slit diaphragm or membrane

 

 

Glomerular capillary basement membrane (BM) of central importance

 

 

Made by epithelial and endothelial cells

 

 

Composed of collagen type IV, glycoproteins and proteoglycans

 

 

No reticular component

 

 

Size barrier: molecules larger than about 69,000 daltons unable to cross

 

 

Charge barrier: proteoglycan component is anionic (negatively charged), therefore repels negatively charged

molecules

 

 

 

Albumin has a molecular weight of 69,000 daltons and is negatively charged

 

 

Mesangium

 

 

Mesangial cells and extracellular matrix (various collagens and ground substance)

 

 

Function

 

 

Supports capillary loops

 

 

Cells have phagocytic function and clean the basement membrane

 

 

May regulate blood flow in capillaries

 

Diabetic nephropathy

 

A clinical syndrome in patients with diabetes mellitus characterised by persistent microalbuminuria, worsening proteinuria,

hypertension and progressive deterioration in renal function. The pathological correlate of diabetic nephropathy is diabetic

 

glomerulosclerosis characterised by a progressive increase in extracellular matrix in the mesangium and capillary basement

 

membranes.

 

 

 

Approximately 25-35% of patients with longstanding diabetes (types 1 and 2) develop diabetic nephropathy and renal failure.

 

 

Diabetic retinopathy often also present, especially in type 1 diabetes

 

 

Clinical and pathological features and progression

 

 

Early:

 

 

Initial increased intraglomerular pressure with hyperfiltration, potentially at least partly related to vasoconstrictor

effect of angiotensin II on efferent arterioles, associated with enlarged glomeruli, commencing within first few years

 

of onset

 

 

 

Microalbuminuria appears 5–10 years after the onset of diabetes

 

 

Later

 

 

Onset of overt proteinuria (10-15 years or more after diabetes onset) +/- nephrotic syndrome +/- hypertension,

beginning deterioration in renal function.

 

 

 

Diffuse and nodular diabetic glomerulosclerosis

 

 

Diffuse

 

 

Diffuse thickening of glomerular capillary BMs (not seen on light microscopy until very thickened)

 

 

Diffuse increase in mesangial matrix +/- mild proliferation of mesangial cells

 

 

Nodular (Kimmelstiel-Wilson lesion)

 

 

Localised nodular areas of increased mesangial matrix with few cells

 

 

Less common than diffuse and generally superimposed on diffuse lesion

 

 

Insudative glomerular lesions: Eosinophilic nodular accumulations of plasma constituents in capillary loops or in

Bowmans capsule

 

 

 

Hyaline arteriolosclerosis in both afferent and efferent arterioles

 

 

Tubular basement membrane thickening

 

 

Immunofluorescence: non-specific (not immunologic) trapping of plasma albumin and IgG in tubular and capillary

basement membranes

 

 

 

Most of the changes are not specific for diabetes

 

 

Mesangial and glomerular capillary BM thickening related to excessive and altered extracellular matrix:

pathogenesis involves accumulation of AGE products, upregulation of growth factors

 

 

 

Glomerular changes -> narrowing of capillary lumina and glomerular ischaemia, hyaline arteriolosclerosis

contributes to glomerular ischaemia.

 

 

 

Hypertension can contribute to glomerular injury.

 

 

Later still: Falling GFR: damaged glomeruli -> impaired renal function. Progressive irreversible glomerulosclerosis,

related tubules atrophy (no blood flow into efferent arterioles and peritubular capillaries) and interstitial tissue undergoes

 

fibrosis -> further impairment of renal function

 

 

 

End stage renal disease: 5-10 years after development of overt proteinuria (or 10-20 years after onset of

microalbuminuria), however, there is considerable variability between patients. Macroscopically the kidneys may be

 

slightly enlarged with a granular surface, or small due to co-existent changes related to hypertension or chronic

 

pyelonephritis.

 

 

 

Pathogenesis of diabetic glomerulosclerosis: complex, at least partly related to microangiopathy (pathogenesis outlined

above)

 

Various pathways implicated, pathways interact

 

 

 

Haemodynamic factors

 

 

Hyperglycaemia -> glomerular hyperfiltration and microalbuminuria, altered tubuloglomerular feedback

 

 

Vasoconstrictor effect of angiotensin II more potent on efferent arteriole -> increased glomerular capillary pressure

and filtration

 

 

 

Hypertension may contribute via glomerular hyperfiltration and endothelial and mesangial damage due to

haemodynamic stress

 

 

 

Metabolic factors e.g. AGE mechanism, activation of protein kinase C

 

 

Hormonal factors: overactive intrarenal renin angiotensin system (RAS), also contributes to development of

hypertension.

 

Effects of angiotensin II in kidney

 

 

 

Sodium and water retention by tubules

 

 

Can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and platelet derived

growth factor (PDGF) systems. TGF-beta-1 stimulates an increase in mesangial matrix deposition and glomerular

 

basement membrane (GBM) thickening

 

 

 

Impairs nitric oxide function which has vasodilatory and protective role

 

 

Can downregulate nephrin, an important protein of the slit diaphragm, leading to proteinuria

 

 

Genetic influences

 

 

Clinical

Progression slowed by good blood glucose control, strict blood pressure control, administration of ACE inhibitors or

 

angiotensin receptor blockers (ARBs) and treatment of dyslipidemia.

 

 

 

Proteinuria and nephrotic syndrome

 

 

Structural alterations in and loss of negative charge of glomerular capillary BM allow albumin to pass through

 

 

Albuminuria is a marker of greatly increased cardiovascular morbidity and mortality for patients with either type 1 or

type 2 diabetes

 

 

 

Hypertension in diabetics

 

 

From diabetic nephropathy

 

 

From chronic renal failure

 

 

Other risk factors e.g. obesity, familial

 

 

Renal artery stenosis (less common)

 

 

Chronic renal failure (CRF)

 

 

Diabetic glomerulosclerosis and hyaline arteriolosclerosis -> chronic glomerular ischaemia -> glomerular

obsolescence/sclerosis and also chronic renal ischaemia with tubular atrophy and interstitial scarring -> poorly

 

functioning kidneys

 

 

 

Approx. 30% of patients develop chronic renal failure

 

 

Chronic pyelonephritis and hypertension may also cause/contribute to CRF

Remember also that diabetics can get other renal diseases.

 

 

Ocular complications

 

Cataracts: from lens swelling and opacity

 

 

Glaucoma: formation of fibrovascular membranes on iris related to ischaemia (from microangiopathy) -> blockage of

outflow channels of aqueous humour

 

 

 

Diabetic retinopathy

 

 

Develops in about 75% within 15 years of disease onset

 

 

More prevalent among patients with type 1 diabetes than type 2

 

 

Often coexists with diabetic nephropathy, but they can also occur independently of each other

 

 

Non-proliferative: microvascular changes with pericyte and also ultimately endothelial cell loss, leads to increases in

vascular permeability, vascular weakening and alterations in retinal blood flow, including blockage of capillaries ->

 

exudates, haemorrhages, microaneurysms, microinfarcts

 

 

 

Macula oedema

 

 

Proliferative: ischaemia from microvascular changes -> proliferation of small vessels, initially on surface of retina

and later into the vitreous -> haemorrhages, fibrosis and retinal detachment.

 

 

 

Increased VEGF expression, contributed to by hypoxia and oxidative stress is important in pathogenesis of

proliferative retinopathy

 

 

 

VEGF is an angiogenic growth factor and increases vascular permeability

 

Neuropathy

 

Distal symmetric sensory or sensorimotor neuropathy

 

 

Symmetric, motor and sensory

 

 

?from Schwann cell injury -> demyelination

 

 

?from axonal injury

 

 

?from microangiopathy impairing blood flow and nutrition of nerve

 

 

Autonomic neuropathy

 

 

-> impotence, bowel and bladder dysfunction etc

 

 

?similar pathogenesis

 

 

Diabetic polyradiculopathy

 

 

Severe disabling pain in the distribution of one or more nerve roots

 

 

May be accompanied by motor weakness

 

 

Focal or multifocal asymmetric neuropathy/mononeuropathy

 

 

Affects larger nerves

 

 

?from microangiopathy impairing blood flow and nutrition of nerve

 

Atherosclerosis

 

Slow build up over years of lipids and fibrous material in the intima of large and medium sized arteries

 

 

In diabetics may extend more distally than usual

 

 

Pathogenesis in diabetes

 

 

Vascular basement membrane and endothelial changes -> increased permeability, trapping of lipids in intima

 

 

Dyslipidaemia

 

 

Hypertension

 

Sources

Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph

Loscalzo, Eds. Harrison’s online: Harrison’s Principles of Internal Medicine, 17th Edition. The McGraw-Hill Companies.

Ahmed N. Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Research and Clinical

Practice 2005: 67: 3–21

Caldwell RB, Bartoli M, Ali Behzadian M, El-Remessy AEB, Al-Shabrawey M. Platt DH, Caldwell RW. Vascular endothelial

growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev

2003; 19: 442–455.

D’ Agati VD, Jennette JC, Silva FG. Non-Neoplastic Kidney Diseases. 2005. American Registry of Pathology Press.

Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin N Am 2004: 88: 1001–1036

Kumar V, Abbas AK, and Fausto N. Robbins and Cotran Pathologic Basis of Disease. 7th edition, 2005. Elsevier Saunders.

Rubin E, Gorstein F, Rubin R, Schwarting R and Strayer D. Rubin’s Pathology Clinicopathologic Foundations of Medicine. 4

 

th

 

edition, 2005. Lippincott Williams and Wilkins

Tsilibary E.C. Microvascular basement membranes in diabetes mellitus. J Pathol 2003; 200: 537–546.

Wilkinson-Berka JL. Angiotensin and diabetic retinopathy. The International Journal of Biochemistry and Cell Biology 2006:

38:752-765


Morphology of Reversible Cell Injury and Necrosis

Cellinjury

  • Two processes cause the basic changes of necrosis: denaturation of proteins, and enzymatic digestion of organelles and cytosol.
  • Autolysis indicates digestion by lysosomal enzymes of the dead cells themselves
  • The necrotic cell is eosinophilic and glassy, maybe vacuolated. The membranes are fragmented. Nuclear changes include pyknosis (small, dense nucleus), karyolysis (faint, dissolved nucleus) and karyorrhexis (broken into bits)
  • Types of necrosis include:
    • coagulative (myocardium, kidney, liver – usually ischaemic)
    • liquefactive (brain and abscesses – autolysis and heterolysis dominate)
    • caseous (tuberculous – soft and cheesy cell debris)
    • fatty (adipose – actions of lipases that decompose triglycerides that complex with calcium to form soaps)

Apoptosis

  • Morphological features include cell shrinkage, chromatin condensation and fragmentation, formation of cytosolic blebs and apoptotic bodies, phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages, and a conspicuous lack of inflammation
  • In many instances, it is dependent on gene activation
  • Occurs in the following settings:
    • programmed cell destruction during embryogenesis
    • hormone-dependent involution (eg. endometrium)
    • cell depletion in proliferating populations
    • pathological atrophy in parenchymal organs after duct obstruction
    • cell death by cytotoxic T cells
    • cell injury from some viral diseases
    • mild traumatic insult

Cellular Adaptation to Injury

  • Atrophy = shrinkage in size by the loss of cell substance
    • causes include decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, aging
    • diminished function but not dead – autophagy, reduced organelles, increased number of autophagic vacuoles; components resisting digestion are deposited as lipofuscin granules, giving a brown appearance
  • Hypertrophy = increase in the size of cells (but not their number)
    • causes include increased functional demand, hormonal stimulation
    • triggered by cell membrane interactions and mechanical factors
  • Hyperplasia = increase in the number of cells
    • can be physiologic (endometrial proliferation, hyperplasia of the liver after lobectomy) or pathologic (almost always excessive hormonal stimulation)
    • when the stimulus is removed, the hyperplasia disappears – this is a crucial difference from neoplasia
  • Metaplasia = a reversible change in which one cell type is replaced by another
    • examples include Barretts’ oesophagus, the respiratory tract of smokers
    • thought to occur from genetic reprogramming

Subcellular Responses

  • Lysosomes are involved in digestion of ingested materials through autophagy and heterophagy. It is pronounced in cells undergoing atrophy. Lysosomes with indigestible material may persist within cells or be extruded.
  • Hypertrophy of the smooth ER, such as by barbiturates, increasing the surface area available for mixed-function oxidase pathway.
  • Mitochondrial alterations, in size, number and function.
  • Cytoskeletal abnormalities, which impede transport of organelles and molecules. The basic cell architecture can be disrupted.
  • Induction of heat shock proteins. These play a role in normal intracellular protein housekeeping (eg. folding them). They are thought to be induced to refold damaged proteins or to tag them for destruction (ubiquitin).
  • Intracellular accumulations – fats (steatosis), cholesterols (atheroma), proteins (Mallory body in alcoholic hepatocytes), glycogen (diabetic renal tubular epithelium), pigments (anthracosis).
  • Pathologic calcification, which implies the abnormal deposition of calcium salts in soft tissues. Dystrophic calcification occurs in nonviable tissue, where metastatic calcification is deposition of calcium salts in vital tissues and is associated with hypercalcaemia (hyperparathyroidism, hypervitaminosis D, sarcoidosis, Addison’s disease, hyperthyroidism, bone cancers).
  • Hyaline change, intracellularly or extracellularly. This is deposition of proteinaceous material that stains a glassy-pink on H&E.
What are the  Diabetic OPN cells ?
 
 
 
 
 
Whate are the   LT-HSCs ?
 
  • Diabetes impairs the interactions between long-term hematopoietic stem cells and osteopontin-positive cells in the endosteal niche of mouse bone marrow
    Hironori Chiba, Koji Ataka, Kousuke Iba, Kanna Nagaishi, Toshihiko Yamashita, Mineko Fujimiya
    October 1, 2013
  • Human-induced pluripotent stem cell-derived cardiomyocytes for studies of cardiac ion transporters
    Michael Fine, Fang-Min Lu, Mei-Jung Lin, Orson Moe, Hao-Ran Wang, Donald W. Hilgemann
    September 1, 2013
  • Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells
    Won Sun Park, Soon Chul Heo, Eun Su Jeon, Da Hye Hong, Youn Kyoung Son, Jae-Hong Ko,Hyoung Kyu Kim, Sun Young Lee, Jae Ho Kim, Jin Han
    August 15, 2013
  • Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction
    Bryon R. McKay, Daniel I. Ogborn, Jeff M. Baker, Kyle G. Toth, Mark A. Tarnopolsky, Gianni Parise
    April 15, 2013
  • Autophagy in endothelial progenitor cells is cytoprotective in hypoxic conditions
    Hai-Jie Wang, Dan Zhang, Yu-Zhen Tan, Ting Li
    April 1, 2013
    SOURCE
    • in vitro model system for smooth muscle differentiation from human embryonic stem cell-derived mesenchymal cells
      Xia Guo, Steven L. Stice, Nolan L. Boyd, Shi-You Chen
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

The

The many cells that make up the blood and immune system

Driwan stem cell information center(continiu)

FOUNDER
 
Dr Iwan Suwandy,MHA
more infocontact
iwansuwandy@ gmail.com
all free of charge
this info to all human in the world
with
 
THE MIGHTY GOD BLESS
 
 
CELL
 
lets we look
how wonderfool and exciting
 
the mighty GOD CREATION
CELL NOT THE SMALLEST P;ART OF OUR BODY BUT
THE BIGGER IMPORTANCE PART OF OUR REGRERATIVE POTIAL
LOOK AND LEARN CAREFULLY
MANY APPARART INSIDE CELL
 
 
 
CELL CONSIST
 
CELL MEMBRANE
with microvilli,
phagocyte vesicle,
cillia and secrotory villia
 
CYTOPLASM
vesicles
peroxisomes
lysosome
lysosome fusin with incoming phagocyte vesicle
mitochondria
free rebosome
golgi apparatus
microtubule network
centrosome and centriole
 
ROUGH ENDOPLASMIC RETICULYM
 
NUCLEUS
 
inside found
NUCLEOLI
 
INSIDE THE APPARAT CONSIST MANY CHEMICAL WHICH
CONTROL OUR REGRENATIVE FUNCTION TO PROTECT OUR CELL FROM
INTERNAL OR EXTERNAL EXPOSUE
CALL
DNA
CCONSIST
 
 
 
 
AGTC
 
ADENINE
 
GUANINE

Thymine

“Thymine (T, Thy)”  

Thymine Structure

Thymine

In our body’s cells, Thymine (T, Thy) is a Pyrimidine derivative, one of the Nitrogenous Bases (Nucleobases) in the Nucleic Acid (Polynucleotide) of DNA. 

Thymine (5-methyluracil)

Thymine (T) is also known as (5-methyluracil).

 

“Thymine → Uracil”  

 

Thymine (T) is also known as (5-methyluracil) and may be derived by methylation of Uracil (U) at the 5th carbon.

 
 

 
THYMINE
 
CYSTOSINE
 
 
FIVE CHEMICAL CHAINS
 
MILLION EXIST
 
 
STILL IN RECSEARXH TO BUILT
 
 
THE HUMONGENOM
 

he human genome is the complete set of genetic information for humans (Homo sapiens).

This information is encoded as DNA sequences within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. Human genomes include both protein-coding DNA genes and noncoding DNAHaploid human genomes (contained in egg and sperm cells) consist of three billion DNA base pairs,

while diploid genomes (found in somatic cells) have twice the DNA content. While there are significant differences among the genomes of human individuals (on the order of 0.1%), these are considerably smaller than the differences between humans and their closest living relatives, the chimpanzees (approximately 4%[1]) and bonobos.

Genomic informations
Karyotype.png

Graphical representation of the idealized human diploid
karyotype, showing the organization of the genome into chromosomes.
This drawing shows both the female (XX) and male (XY) versions of the
23rd chromosome pair. Chromosomes are shown aligned at their

centromeres. The mitochondrial DNA is not shown.

 NCBI Genome Id.   51
 Ploidy.   diploid
 Genome size.   3,234.83 Mb
 Number of chromosomes.   23 pairs  

The Human Genome Project produced the first complete sequences of individual human genomes. As of 2012, thousands of human genomes have been completely sequenced, and many more have been mapped at lower levels of resolution. The resulting data are used worldwide in biomedical scienceanthropologyforensics and other branches of science. There is a widely held expectation that genomic studies will lead to advances in the diagnosis and treatment of diseases, and to new insights in many fields of biology, including human evolution.

Although the sequence of the human genome has been (almost) completely determined by DNA sequencing, it is not yet fully understood. Most (though probably not all) genes have been identified by a combination of high throughput experimental andbioinformatics approaches, yet much work still needs to be done to further elucidate the biological functions of their protein and RNA products. Recent results suggest that most of the vast quantities of noncoding DNA within the genome have associated biochemical activities, including regulation of gene expression, organization of chromosome architecture, and signals controlling epigenetic inheritance.

The haploid human genome contains approximately 20,000 protein-coding genes, significantly fewer than had been anticipated.[2][3]Protein-coding sequences account for only a very small fraction of the genome (approximately 1.5%), and the rest is associated with non-coding RNA molecules, regulatory DNA sequencesLINEsSINEsintrons, and sequences for which as yet no functionhas been elucidated.[4]

 
AND
 
 
RNA
IF THE SYSTEM CANNOT REVANCE ADAINS THE EXPOSURE WE BECAME SICK AND OUR CELL AND THE SYSTEM BECAM DAMGE FASTLY BECAME ACUTE DISEASE
AND SLWLY BECAME CHRONIC DISEASE
WHEM W WE SURVIVE AND BECAME OLDER
THE SYSTEMIC STARTING TO DEGRETIV AGING
WE MUST PROTECT WITH
STEM CELL OR GENETIC REGERATION
 
 
 gen therapy more difficullt
 
like many years research still not many found like indonesian eijkman lab by prof DR Sangkot done
 
better to used
stem cell
 
is basically any cell that can replicate and differentiate.
This means the cell can not only multiply,
it can turn into different types of tissues.
 
 
There are different kinds of stem cells.

All Stem Cells Have Three Main Properties:

1. They can divide and renew themselves for extended periods of time.

2. They can morph into specialized cell types.

LIKE

cancer stem cell

liver ca stem cell

 

skin stem cell control eilepsy

 

 hemopoetic stem cell

pancreas stem cell

renal stem cell

 

cardiac stem cell

 

3. They are unspecialized (which allows them to be a blank slate for morphing into specialized cells).

There are three main types of stem cells and, depending on the source, they are all harvested differently.

1. “embryonic stem cell.”

 
 
 
Most people are familiar with or have heard the term “embryonic stem cell.”
 
These are cells from the embryonic stage
 
2the “pluri-potential” cells
 
 
 
that have yet to differentiate – as such, they can change into any body part at all.
 
These are then called “pluri-potential” cells.
Because they are taken from unborn or unwanted embryos, there has been considerable controversy surrounding their use.
 
3.the “adult stem cell.”
 
 
Another kind of stem cell is the “adult stem cell.”
 
This is a stem cell that already resides in one’s body within different tissues.
 
a. In recent times, much work has been done isolating bone-marrow derived stem cells.
 
b.These are also known as
 
 
 
“mesenchymal stem cells”
because they come from
1) the mesodermal section of your body.
 
2)They can differentiate into
a)bone and cartilage,
b)and probably all other mesodermal elements,
such as
(1) fat tissue
(2), connective tissue
(3), blood vessels,
(4) muscle
(5) and nerve tissue.
 
hemopoetic stem ceel
 
 
 
 
 
WHAT WERE THE DFFERENCE BETWEEN  EMBRIONIC  AND ADULT STEM CELL?
 
 
 
A.DIFFERENT EXPANTION
 
1) EMBRYONIC STEM CELL
WHOLE BONE MARROW  DERIVED NESENCHYMAL,HEMOPOETIC AND ENDOTHELIA PROGENITOR TRANSCRIPT FACTOR MICRO RNA’S REPROGRAMMING(B) TO REPAIR CELL
 
2)ADULT STEM CELL
 
BISIDE EMBRYONIC STEM CELL
PLUS ADDED HUMORAL FACTOR HOMING(D) TO REPAIR CELL
1)CIRCULATING STEM CELL
2)RESIDENT STEM CELL
3)FIBROBLAST
 
 
 
WHAT IS THE PROBLEM OF STEM CELL THERAPY?
 

This will depend on the type of degenerative condition you have.

A specialist will evaluate you and discuss whether you’re a potential candidate for stem cell therapy.

If after you’ve been recommended for treatment, had an opportunity to understand the potential risks and benefits, and decided on your own that you would like to explore this avenue of treatment, then you can be considered for treatment.

Of course, even though it’s a minimally invasive procedure, you will still need to be medically cleared for the procedure.

a potential candidate for stem cell therapy.

Stem Cell Therapy For Joint And Soft Tissue Injuries

Stem Cells Therapy Is Helping People With Their Golf Game

Dr. Brandt is one of a select few physicians in the country to be trained in a groundbreaking, minimally invasive technique that is saving many patients from undergoing difficult joint replacement surgery. 

Stem cell therapy relies on the body’s own natural healing abilities to repair tissue in affected joints. This technique begins by taking a patient’s own stem cells found in adipose (fat) tissue, concentrating the cells into a small injection, and then reintroducing them into the area of concern.

This process stimulates the body to repair and replace tissue that has disintegrated over time or been traumatized from injury or overuse.

 

How does Adult Stem Cell Therapy work ?

Cell therapy is simply helping your body do what is does naturally.

If you get a cut on your skin, stem cells in your blood go to that cut. They lodge in the damaged tissue and receive signals from the adjacent damaged tissue.

The stem cell responds

by sending out it own signals to the body.

It requests materials,

like proteins,

to rebuild what was damaged,

to regenerate the tissue,

the natural healing process.

Modern stem cell therapy is the process of finding the adult stem cells that are best at repairing specific damaged tissue, be it vascular, heart, neurological, pancreas, etc.

These specific cells are isolated in the lab, cultured, multiplied and activated.

They are your repair cells, your DNA and know how to fix you.

Then the doctor puts them back into your body, targeted to the damaged tissue.

This can be by IV, direct injection into the heart muscle, direct injection into damaged spinal cord, direct injection into the pancreas or direct injection into the area of the brain damaged by stroke.

The stem cells can do two things. Differentiate and mature into that type of tissue – a nerve cell, heart muscle, cartilage or whatever.

They can also help support other cells resident in that tissue to mature into healthy cells. In some case both situations may occur. This process is still being investigated and holds the key to future medical treatments. One thing for sure is that adult stem cell therapy is being used today to treat somebody with a similar condition you are concerned about. Contact us and we can help guide you to the best available therapy today

Is Adult Stem Cell Therapy safe ?

Yes, autologous stem cell procedures for adult stem cell therapy are totally safe as the cells come from your own body.

There cannot be any problems of rejection because they carry the patient’s own DNA.

 

How are the stem cells taken from the body and what happens ?

A small amount of tissue is taken from bone marrow, blood, fat, or skin.
The procedure is simple and minimally invasive.
This sample is then sent to a laboratory where the stem cells that are needed are isolated and harvested into the many millions that are required to be therapeutically effective.
 

How did I feel after treatment ?

Stem cell therapy is your body repairing itself. Immediately after treatment patients usually feel the same, maybe a little more optimistic about their recovery. Again, depending on your condition, for some neurological conditions patients have seen improvement in a matter of days and felt better. For example, slurred speech improvement or tremors. Doctors will tell patients the body usually takes 3-6 months for cellular repair activity to take place in damaged tissue or organs. Check out what patients have to say that have your condition.