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1.  Chromatin-Modifying Agents Reactivate Embryonic Renal Stem/Progenitor Genes in Human Adult Kidney Epithelial Cells but Abrogate Dedifferentiation and Stemness 
Cellular Reprogramming  2013;15(4):281-292.
Abstract
Recent studies have suggested that epigenetic modulation with chromatin-modifying agents can induce stemness and dedifferentiation and increase developmental plasticity. For instance, valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been shown to promote self-renewal/expansion of hematopoietic stem cells and facilitate the generation of induced pluripotent stem cells (iPSCs). Previously, we observed that downregulation of embryonic renal stem/progenitor genes in the adult kidney was associated, at least in part, with epigenetic silencing. Therefore, we hypothesized that VPA may alter the expression of these genes and reprogram mature human adult kidney epithelial cells (hKEpCs) to a stem/progenitor-like state.
Here, using quantitative RT-PCR and flow cytometry [fluorescence-activated cell sorting (FACS)] analysis, we show in VPA-treated primary cultures of human adult and fetal kidney significant reinduction of the renal stem/progenitor markers SIX2, OSR1, SALL1, NCAM, and PSA-NCAM. Robust SIX2 mRNA re-expression was confirmed at the protein level by western blot and was associated with epigenetic changes of the histones at multiple sites of the SIX2 promoter leading to gene activation, significantly increased acetylation of histones H4, and methylation of lysine 4 on H3. Furthermore, we could demonstrate synergistic effects of VPA and Wnt antagonists on SIX2 and also OSR1 reinduction. Nevertheless, VPA resulted in upregulation of E-CADHERIN and reduction in VIMENTIN, preventing the skewing of hKEpCs towards a more replicative mesenchymal state required for clonogenic expansion and acquisition of stem cell characters, altogether inducing cell senescence at early passages. These results demonstrating that chromatin-modifying agents prevent dedifferentiation of hKEpCs have important clinical implications as they may limit ex-vivo self-renewal/expansion and possibly the in vivo renal regenerative capacity initiated by dedifferentiation.
doi:10.1089/cell.2012.0087
PMCID: PMC3725946  PMID: 23841748
2.  Wilms’ Tumor Blastemal Stem Cells Dedifferentiate to Propagate the Tumor Bulk 
Stem Cell Reports  2014;3(1):24-33.
Summary
An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms’ tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1+) aldehyde dehydrogenase 1-positive (ALDH1+) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1+ WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.
Graphical Abstract
Highlights
•The Wilms’ tumor (WT) blastema can be exclusively propagated in mice•Gene and protein analyses place the WT CSC at a specific developmental stage•WT CSCs do not correspond to the earliest renal stem cells•WT CSCs are likely to dedifferentiate to propagate WT blastema
The developmental status of cancer stem cells (CSCs) remains obscure. Wilms’ tumors (WT) are composed of blastema and differentiated renal elements. Herein, by generating pure blastema WT xenografts, Shukrun et al. surprisingly show that sorted NCAM+ALDH1+ WT CSCs do not correspond to the earliest renal stem cells. Rather, the authors show that they are skewed toward epithelial differentiation compared to the blastema bulk. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.
doi:10.1016/j.stemcr.2014.05.013
PMCID: PMC4110791  PMID: 25068119
3.  A Human Integrin-α3 Mutation Confers Major Renal Developmental Defects 
PLoS ONE  2014;9(3):e90879.
The development of the mammalian kidney is a highly complex process dependent upon the interplay of various cell types, secreted morphogens, and the extra-cellular matrix (ECM). Although integrins are the most important receptors for ECM proteins and are ubiquitously expressed during kidney development, mice lacking expression of integrin α3 (Itga3) do not demonstrate a reduced number of nephrons, but mostly a disorganized GBM (glomerular basement membrane) leading to proteinuria. Thus, ITGA3 is considered mostly a passive GBM stabilizer and not an active player in nephrogenesis. Recently, mutations in the human ITGA3 were shown to cause congenital nephrotic syndrome, epidermolysis bullosa and interstitial lung disease, otherwise termed NEP syndrome (Nephrotic syndrome, Epidermolysis bullosa and Pulmonary disease). Herein, we performed histological and molecular analysis on the kidneys of a single patient from the initial cohort harboring an ITGA3 mutation, to illuminate the role of ITGA3 in human renal development. We show the patient to harbor a unique phenotype at birth, including severe unilateral renal hypodysplasia. Interrogation of global gene expression in the hypodysplastic kidney versus three controls (fetal, child and adult kidneys) revealed perturbed expression in several renal developmental pathways implicated in hypodysplasia, including the Wnt, BMP (bone morphogenetic protein) and TGF (transforming growth factor) pathways. Moreover, the affected kidney showed upregulation of early embryonic genes (e.g. OCT4 and PAX8) concomitant with downregulated kidney differentiation markers, implying a defect in proper renal differentiation. In conclusion, we show for the first time that ITGA3 is not merely a passive anchor for renal ECM proteins, as predicted by mouse models. Instead, our results may suggest it plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes.
doi:10.1371/journal.pone.0090879
PMCID: PMC3951280  PMID: 24621570
4.  Identification of human nephron progenitors capable of generation of kidney structures and functional repair of chronic renal disease 
EMBO Molecular Medicine  2013;5(10):1556-1568.
Identification of tissue-specific renal stem/progenitor cells with nephrogenic potential is a critical step in developing cell-based therapies for renal disease. In the human kidney, stem/progenitor cells are induced into the nephrogenic pathway to form nephrons until the 34 week of gestation, and no equivalent cell types can be traced in the adult kidney. Human nephron progenitor cells (hNPCs) have yet to be isolated. Here we show that growth of human foetal kidneys in serum-free defined conditions and prospective isolation of NCAM1+ cells selects for nephron lineage that includes the SIX2-positive cap mesenchyme cells identifying a mitotically active population with in vitro clonogenic and stem/progenitor properties. After transplantation in the chick embryo, these cells—but not differentiated counterparts—efficiently formed various nephron tubule types. hNPCs engrafted and integrated in diseased murine kidneys and treatment of renal failure in the 5/6 nephrectomy kidney injury model had beneficial effects on renal function halting disease progression. These findings constitute the first definition of an intrinsic nephron precursor population, with major potential for cell-based therapeutic strategies and modelling of kidney disease.
doi:10.1002/emmm.201201584
PMCID: PMC3799579  PMID: 23996934
development; kidney stem cells; progenitor cells; regeneration; stem cells
5.  The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets† 
EMBO Molecular Medicine  2012;5(1):18-37.
There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets.
doi:10.1002/emmm.201201516
PMCID: PMC3569651  PMID: 23239665
cancer initiating cells; cancer stem cells; kidney stem cells; renal progenitor cells; targeted therapy
6.  Integrin α3 Mutations with Kidney, Lung, and Skin Disease 
The New England Journal of Medicine  2012;366(16):1508-1514.
SUMMARY
Integrin α3 is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin α3 gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.
doi:10.1056/NEJMoa1110813
PMCID: PMC3341404  PMID: 22512483
7.  Selecting the optimal cell for kidney regeneration 
Organogenesis  2011;7(2):123-134.
Chronic kidney disease (CKD) is a progressive loss in renal function over a period of months or years. End-stage renal disease (ESRD) or stage 5 CKD ensues when renal function deteriorates to under 15% of the normal range. ESRD requires either dialysis or, preferentially, a kidney organ allograft, which is severely limited due to organ shortage for transplantation. To combat this situation, one needs to either increase supply of organs or decrease their demand. Two strategies therefore exist: for those that have completely lost their kidney function (ESRD), we will need to supply new kidneys. Taking into account the kidneys' extremely complex structure, this may prove to be impossible in the near future. In contrast, for those patients that are in the slow progression route from CKD to ESRD but still have functional kidneys, we might be able to halt progression by introducing stem cell therapy to diseased kidneys to rejuvenate or regenerate individual cell types. Multiple cell compartments that fall into three categories are likely to be worthy targets for cell repair: vessels, stroma (interstitium) and nephron epithelia. Different stem/progenitor cells can be linked to regeneration of specific cell types; hematopoietic progenitors and hemangioblastic cell types have specific effects on the vascular niche (vasculogenesis and angiogenesis). Multipotent stromal cells (MSC), whether derived from the bone marrow or isolated from the kidney's non-tubular compartment, may, in turn, heal nephron epithelia via paracrine mechanisms. Nevertheless, as we now know that all of the above lack nephrogenic potential, we should continue our quest to derive genuine nephron (epithelial) progenitors from differentiated pluripotent stem cells, from fetal and adult kidneys and from directly reprogrammed somatic cells.
doi:10.4161/org.7.2.15783
PMCID: PMC3142449  PMID: 21519195
kidney regeneration; kidney stem cells; surface markers; reprogramming; tissue specific stem cells; renal progenitors
8.  A rapid in vivo assay system for analyzing the organogenetic capacity of human kidney cells 
Organogenesis  2011;7(2):140-144.
Transplantation of human kidney-derived cells is a potential therapeutic modality for promoting regeneration of diseased renal tissue. However, assays that determine the ability of candidate populations for renal cell therapy to undergo appropriate differentiation and morphogenesis are limited. We report here a rapid and humane assay for characterizing tubulogenic potency utilizing the well-established chorioallantoic membrane (CAM) of the chick embryo.
Adult human kidney-derived cells expanded in monolayer were suspended in Matrigel and grafted onto the CAM. After a week, grafts were assessed histologically. Strikingly, many of the renal cells self-organized into tubular structures. Host blood vessels penetrated and presumably fed the grafts. Immuno- and histochemical staining revealed that tubular structures were epithelial, but not blood vessels. Some of the cells both within and outside the tubules were dividing. Analysis for markers of proximal and distal renal tubules revealed that grafts contained individual cells of a proximal tubular phenotype and many tubules of distal tubule character.
Our results demonstrate that the chick CAM is a useful xenograft system for screening for differentiation and morphogenesis in cells with potential use in renal regenerative medicine.
doi:10.4161/org.7.2.16457
PMCID: PMC3142451  PMID: 21613816
xenograft; kidney development; transplantation therapy; chorioallantoic membrane; renal progenitors
9.  Correction: Expression of Stem Cell Markers in the Human Fetal Kidney 
PLoS ONE  2011;6(3):10.1371/annotation/5c42ca40-0a01-4e4e-94e3-ccaa2cc54fc6.
doi:10.1371/annotation/5c42ca40-0a01-4e4e-94e3-ccaa2cc54fc6
PMCID: PMC3068038
10.  Expression of Stem Cell Markers in the Human Fetal Kidney 
PLoS ONE  2009;4(8):e6709.
In the human fetal kidney (HFK) self-renewing stem cells residing in the metanephric mesenchyme (MM)/blastema are induced to form all cell types of the nephron till 34th week of gestation. Definition of useful markers is crucial for the identification of HFK stem cells. Because wilms' tumor, a pediatric renal cancer, initiates from retention of renal stem cells, we hypothesized that surface antigens previously up-regulated in microarrays of both HFK and blastema-enriched stem-like wilms' tumor xenografts (NCAM, ACVRIIB, DLK1/PREF, GPR39, FZD7, FZD2, NTRK2) are likely to be relevant markers. Comprehensive profiling of these putative and of additional stem cell markers (CD34, CD133, c-Kit, CD90, CD105, CD24) in mid-gestation HFK was performed using immunostaining and FACS in conjunction with EpCAM, an epithelial surface marker that is absent from the MM and increases along nephron differentiation and hence can be separated into negative, dim or bright fractions. No marker was specifically localized to the MM. Nevertheless, FZD7 and NTRK2 were preferentially localized to the MM and emerging tubules (<10% of HFK cells) and were mostly present within the EpCAMneg and EpCAMdim fractions, indicating putative stem/progenitor markers. In contrast, single markers such as CD24 and CD133 as well as double-positive CD24+CD133+ cells comprise >50% of HFK cells and predominantly co-express EpCAMbright, indicating they are mostly markers of differentiation. Furthermore, localization of NCAM exclusively in the MM and in its nephron progenitor derivatives but also in stroma and the expression pattern of significantly elevated renal stem/progenitor genes Six2, Wt1, Cited1, and Sall1 in NCAM+EpCAM- and to a lesser extent in NCAM+EpCAM+ fractions confirmed regional identity of cells and assisted us in pinpointing the presence of subpopulations that are putative MM-derived progenitor cells (NCAM+EpCAM+FZD7+), MM stem cells (NCAM+EpCAM-FZD7+) or both (NCAM+FZD7+). These results and concepts provide a framework for developing cell selection strategies for human renal cell-based therapies.
doi:10.1371/journal.pone.0006709
PMCID: PMC2725321  PMID: 19696931
11.  Analysis of circulating hem-endothelial marker RNA levels in preterm infants 
BMC Pediatrics  2009;9:42.
Background
Circulating endothelial cells may serve as novel markers of angiogenesis. These include a subset of hem-endothelial progenitor cells that play a vital role in vascular growth and repair. The presence and clinical implications of circulating RNA levels as an expression for hematopoietic and endothelial-specific markers have not been previously evaluated in preterm infants. This study aims to determine circulating RNA levels of hem-endothelial marker genes in peripheral blood of preterm infants and begin to correlate these findings with prenatal complications.
Methods
Peripheral blood samples from seventeen preterm neonates were analyzed at three consecutive post-delivery time points (day 3–5, 10–15 and 30). Using quantitative reverse transcription-polymerase chain reaction we studied the expression patterns of previously established hem-endothelial-specific progenitor-associated genes (AC133, Tie-2, Flk-1 (VEGFR2) and Scl/Tal1) in association with characteristics of prematurity and preterm morbidity.
Results
Circulating Tie-2 and SCL/Tal1 RNA levels displayed an inverse correlation to gestational age (GA). We observed significantly elevated Tie-2 levels in preterm infants born to mothers with amnionitis, and in infants with sustained brain echogenicity on brain sonography. Other markers showed similar expression patterns yet we could not demonstrate statistically significant correlations.
Conclusion
These preliminary findings suggest that circulating RNA levels especially Tie2 and SCL decline with maturation and might relate to some preterm complication. Further prospective follow up of larger cohorts are required to establish this association.
doi:10.1186/1471-2431-9-42
PMCID: PMC2709108  PMID: 19555479
12.  Embryonic Pig Pancreatic Tissue Transplantation for the Treatment of Diabetes 
PLoS Medicine  2006;3(7):e215.
Background
Transplantation of embryonic pig pancreatic tissue as a source of insulin has been suggested for the cure of diabetes. However, previous limited clinical trials failed in their attempts to treat diabetic patients by transplantation of advanced gestational age porcine embryonic pancreas. In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages.
Methods and Findings
Implantation of embryonic pig pancreatic tissues of different gestational ages in SCID mice reveals that embryonic day 42 (E42) pig pancreas can enable a massive growth of pig islets for prolonged periods and restore normoglycemia in diabetic mice. Furthermore, both direct and indirect T cell rejection responses to the xenogeneic tissue demonstrated that E42 tissue, in comparison to E56 or later embryonic tissues, exhibits markedly reduced immunogenicity. Finally, fully immunocompetent diabetic mice grafted with the E42 pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti–CD40 ligand (anti-CD40L) attained normal blood glucose levels, eliminating the need for insulin.
Conclusions
These results emphasize the importance of selecting embryonic tissue of the correct gestational age for optimal growth and function and for reduced immunogenicity, and provide a proof of principle for the therapeutic potential of E42 embryonic pig pancreatic tissue transplantation in diabetes.
Editors' Summary
Background.
Diabetes is a growing global health problem. By 2030, more than 300 million people around the world will have this chronic, incurable disorder, double the current number. In non-diabetic people, cells in the pancreas called beta cells release insulin, a hormone that controls the level of sugar (glucose) in the blood. In diabetics, blood-sugar levels become dangerously high either because the beta cells have been destroyed so no insulin is made (type 1 diabetes, 5%–10% of all cases) or because the cells that normally remove sugar from the blood have become insensitive to insulin (type 2 diabetes). In particularly severe cases of type 2 diabetes, the beta cells also stop releasing insulin. People with type 2 diabetes can usually control their blood-sugar levels through diet and exercise and by taking oral anti-diabetic drugs; people with type 1 diabetes or severe type 2 diabetes have to replace the missing insulin by injections. It is very important that diabetics keep their blood-sugar levels as normal as possible to minimize the disorder's serious long-term complications. These include kidney failure, blindness, nerve damage, and an increased risk of heart disease and strokes.
Why Was This Study Done?
While individuals with type 1 diabetes can control their blood-sugar levels pretty well by carefully monitoring their life style and injecting insulin, potentially better control and fewer long-term complications can be achieved by providing a new source of insulin-producing cells through transplantation of pancreatic tissue from a dead human donor. However, because there is not enough human pancreatic tissue to treat all the diabetics who could benefit from such transplants, researchers are investigating other sources of insulin-producing cells. One possibility is pig pancreatic tissue. Glucose control is very similar in pigs and humans, pig insulin injections have been used for years to control diabetes, and pigs are in plentiful supply. However, besides general concerns about xenotransplantation (that is, transplantation from a foreign species such as pigs into humans), early attempts to treat human diabetes by transplantation of pancreatic tissue taken from pig embryos at late stages of gestation were not successful. The researchers involved in this study had done earlier experiments that suggested that the age of the pig donor tissue influences how well transplantation into other species works. They therefore wanted to test whether pancreatic tissue from younger pig embryos might work better for pancreas transplants: they hoped that younger tissue would grow and integrate better with the surrounding host tissue. Additionally, a major concern with all transplantations is whether the transplanted cells or tissue will be recognized as foreign and as such destroyed by the host's immune system. Because tissue from younger embryos is generally less likely to trigger an immune reaction, the researchers hoped that pancreatic tissue from younger pig embryos would be less readily recognized as foreign by the human immune system.
What Did the Researchers Do and Find?
They started by transplanting pancreatic tissue from pig embryos of different ages into mice with defective immune systems. Tissue taken about a third of the way through gestation (that is, from embryos 42 or 56 days old) grew better than tissue taken earlier or later, secreted more pig insulin over extended periods of time, and was better at maintaining normal blood-sugar levels when the beta cells of the host mice were destroyed. The researchers then examined whether embryonic pig pancreatic tissue of different ages triggered an immune reaction by seeing how well it survived when human immune system cells were also transplanted into the mice. Tissue from 42-day-old embryos came out best in this test too, suggesting that there is little or no “direct” immune reaction by circulating immune cells against pancreatic tissue from this stage. Finally, the researchers transplanted pancreatic tissue of this age into diabetic mice with an intact immune system. These mice rejected the transplants (presumably through an “indirect” immune reaction), but that rejection could be overcome when the recipient mice were treated with drugs that suppressed the part of their immune system that is responsible for these indirect immune reactions. (Human patients who receive a transplant are usually treated with drugs that suppress direct and indirect immune reactions.) When the mice were kept on the drugs, the grafts survived in the long term, and the mice had normal blood-sugar levels once the graft was well established.
What Do These Findings Mean?
These results suggest that the exact age of embryonic pig pancreatic tissue influences how well the transplanted tissue grows and integrates into a host from a different species (in this case, the mouse) and how strong an immune reaction it triggers. Overall, these results support the notion that pig embryonic pancreas tissue could potentially be a source of tissue for transplantation into human patients with diabetes. The next steps in exploring this possibility are likely to involve experiments in monkeys to find out how much tissue should be implanted and where, and to check that the transplanted tissue remains functional in these animals. The ability of the 42-day-old embryonic tissue to avoid direct immune rejection also needs to be confirmed. And, ideally, the goal remains to find ways to avoid an immune reaction altogether, so that recipients of transplants do not need to be continually treated with drugs that suppress their immune system (which makes them more susceptible to infections and can have other side effects). Xenotransplantation has potential benefits and risks and remains controversial. Studies like this one and others that seek to better understand the risks and benefits are necessary to allow reasonable decisions to be made.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030215
• MedlinePlus pages on diabetes and on pancreas transplantation
• Information from the Juvenile Diabetes Research Foundation International Description
• Wikipedia pages on diabetes, xenotransplantation, and pancreas transplantation (note: Wikipedia is a free online encyclopedia that anyone can edit)
Pancreatic tissue from embryonic pigs co-transplanted with or without human immune cells into immune-deficient mice suggests that the embryonic stage of the pig donor affects the immunogenicity of the graft.
doi:10.1371/journal.pmed.0030215
PMCID: PMC1479387  PMID: 16768546
13.  Transcriptional Link between Blood and Bone: the Stem Cell Leukemia Gene and Its +19 Stem Cell Enhancer Are Active in Bone Cells 
Molecular and Cellular Biology  2006;26(7):2615-2625.
Blood and vascular cells are generated during early embryogenesis from a common precursor, the hemangioblast. The stem cell leukemia gene (SCL/tal 1) encodes a basic helix-loop-helix transcription factor that is essential for the normal development of blood progenitors and blood vessels. We have previously characterized a panel of SCL enhancers including the +19 element, which directs expression to hematopoietic stem cells and endothelium. Here we demonstrate that SCL is expressed in bone primordia during embryonic development and in adult osteoblasts. Despite consistent expression in cells of the osteogenic lineage, SCL protein is not required for bone specification of embryonic stem cells. In transgenic mice, the SCL +19 core enhancer directed reporter gene expression to vascular smooth muscle and bone in addition to blood and endothelium. A 644-bp fragment containing the SCL +19 core enhancer was active in both blood and bone cell lines and was bound in vivo by a common array of Ets and GATA transcription factors. Taken together with the recent observation that a common progenitor can give rise to blood and bone cells, our results suggest that the SCL +19 enhancer targets a mesodermal progenitor capable of generating hematopoietic, vascular, and osteoblastic progeny.
doi:10.1128/MCB.26.7.2615-2625.2006
PMCID: PMC1430329  PMID: 16537906
14.  Concise Review: Kidney Stem/Progenitor Cells: Differentiate, Sort Out, or Reprogram? 
Stem Cells (Dayton, Ohio)  2010;28(9):1649-1660.
End-stage renal disease (ESRD) is defined as the inability of the kidneys to remove waste products and excess fluid from the blood. ESRD progresses from earlier stages of chronic kidney disease (CKD) and occurs when the glomerular filtration rate (GFR) is below 15 ml/minute/1.73 m2. CKD and ESRD are dramatically rising due to increasing aging population, population demographics, and the growing rate of diabetes and hypertension. Identification of multipotential stem/progenitor populations in mammalian tissues is important for therapeutic applications and for understanding developmental processes and tissue homeostasis. Progenitor populations are ideal targets for gene therapy, cell transplantation, and tissue engineering. The demand for kidney progenitors is increasing due to severe shortage of donor organs. Because dialysis and transplantation are currently the only successful therapies for ESRD, cell therapy offers an alternative approach for kidney diseases. However, this approach may be relevant only in earlier stages of CKD, when kidney function and histology are still preserved, allowing for the integration of cells and/or for their paracrine effects, but not when small and fibrotic end-stage kidneys develop. Although blood- and bone marrow-derived stem cells hold a therapeutic promise, they are devoid of nephrogenic potential, emphasizing the need to seek kidney stem cells beyond known extrarenal sources. Moreover, controversies regarding the existence of a true adult kidney stem cell highlight the importance of studying cell-based therapies using pluripotent cells, progenitor cells from fetal kidney, or dedifferentiated/reprogrammed adult kidney cells. Stem Cells 2010; 28:1649–1660.
doi:10.1002/stem.486
PMCID: PMC2996087  PMID: 20652959
Adult stem cells; Kidney; Cell surface markers; Cellular therapy; Developmental biology; Embryonic stem cells; Fetal stem cells

Results 1-14 (14)