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.
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- Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
- 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;firstname.lastname@example.org; Web: www.imb.uq.edu.au
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),
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
As in most organs, bone marrow–derived cells (BMDC) appear in the kidney in response to damage.
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 (22–24).
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.