BRIEF REVIEW www.jasn.org Glomerular Epithelial Stem Cells: The Good, The Bad, and The Ugly Laura Lasagni* and Paola Romagnani*† *Excellence Centre for Research, Transfer and High Education for the development of De Novo Therapies (DENOTHE), University of Florence, Florence, Italy; and †Pediatric Nephrology Unit, Meyer University Hospital, Florence, Italy ABSTRACT Global glomerulosclerosis with loss of podocytes in humans is typical of end- ing podocyte number.23–25 Because resi- stage renal pathology. Although mature podocytes are highly differentiated dent podocytes do not divide, this sug- and nondividing, converging evidence from experimental and clinical data gests that new podocytes derive by suggests adult stem cells within Bowman’s capsule can rescue some of this loss. regeneration. Regression of renal disease Glomerular epithelial stem cells generate podocytes during kidney growth and with remodeling of glomerular architec- regenerate podocytes after injury, thus explaining why various glomerular ture is observed in pancreatic transplant disorders undergo remission occasionally. This regenerative process, however, patients with type 1 diabetes after 10 is often inadequate because of inefficient proliferative responses by glomerular years of normoglycemia26 and in patients epithelial stem cells with aging or in the setting of focal segmental glomerulo- treated chronically with angiotensin- sclerosis. Alternatively, an excessive proliferative response by glomerular epi- converting enzyme inhibitors.23–27 thelial stem cells after podocyte injury can generate new lesions such as Taken together, these results imply there extracapillary crescentic glomerulonephritis, collapsing glomerulopathy and tip are stem cells in adult glomeruli with the lesions. Better understanding of the mechanisms that regulate growth and potential to regenerate podocytes. differentiation of glomerular epithelial stem cells may provide new clues for prevention and treatment of glomerulosclerosis. J Am Soc Nephrol 21: 1612–1619, 2010. doi: 10.1681/ASN.2010010048 THE GOOD: GLOMERULAR EPITHELIAL STEM CELLS REGENERATE PODOCYTES Global glomerulosclerosis in humans ac- glomerulosclerosis (FSGS).1,8–13 Fi- companies most progressive renal pa- nally, mutations that produce a glomer- Stem cells are functionally defined by thology. Although primary injury to each ulosclerosis occur exclusively among their ability to self-renew and differenti- of the somatic cell types in the glomeru- genes expressed by the podocyte.14–16 ate into cell lineages reflecting their tissue 21 lar tuft associates with some form of glo- Interestingly, depletion of highly spe- of origin. The ability to self-renew stem merular disease, injury to endothelial cialized cells with limited capacity to di- cells is maintained by a process called and mesangial cells repair by prolifera- vide is a common pathway driving many symmetric division, where new daughter tion of adjacent cells.1,2 By contrast, types of organ failure.17–20 In other adult cells maintain all the functional and phe- 21 podocytes are highly differentiated, neu- organs, loss of highly specialized cells notypic properties of stem cells. How- ron-like cells that cannot divide,1,2 which during injury can be replaced by resident ever, once activated, stem cells can also explains why podocyte injury is a key stem cells.21,22 For example, neuronal cell regenerate by asymmetric division, pro- driver of focal or global glomerulosclero- depletion after ischemic injury generates ducing a daughter stem cell and a com- sis.3 Indeed, a large body of evidence brain dysfunction, but neuronal stem from experimental models suggests loss cells in the adult brain also drive replace- Published online ahead of print. Publication date of podocytes over a certain threshold in- ment of lost neurons with some func- available at www.jasn.org. duces glomerulosclerosis.2–7 Podocyte tional recovery.22 Accordingly, severe Correspondence: Dr. Paola Romagnani, Depart- number is also reduced in proportion to podocyte loss and glomerulosclerosis ment of Clinical Pathophysiology, Nephrology Section, University of Florence, Viale Pieraccini 6, the severity of injury and degree of pro- can be rescued occasionally by replace- 50139 Firenze, Italy. Phone: ϩ39554271356; Fax: teinuria, and predicts progression in ment.23–27 Data from experimental mod- ϩ39554271357; E-mail: [email protected] patients with diabetic nephropathy, els also demonstrate that regression of Copyright © 2010 by the American Society of IgA nephropathy, and focal segmental glomerulosclerosis can occur by increas- Nephrology 1612 ISSN : 1046-6673/2110-1612 J Am Soc Nephrol 21: 1612–1619, 2010 www.jasn.org BRIEF REVIEW mitted progenitor.21 In their normal envi- ronment, committed progenitors retain the capacity to divide and differentiate to- ward a particular lineage. Urinary pole Recently, we provided the first evidence C Detaching that adult human glomeruli contain a hier- podocytes archical population of stem and commit- A ted progenitor cells.28–33 These resident stem and progenitor cells localize within B the Bowman’s capsule and are identified by the presence of both CD24 and CD133, two surface molecules that are shared by different types of human adult ϩ ϩ stem cells.34,35 CD24 , CD133 cells lo- calize at the urinary pole of Bowman’s capsule and exhibit self-renewal proper- Vascular stalk ties and also the potential to differentiate into podocytes or proximal tubular cells (Figure 1).33 Clonal analyses demon- strate this subset of parietal epithelial cells represent multipotent epithelial stem cells and not simply a mixture of Figure 1. The good: Glomerular epithelial stem cells regenerate podocytes. Glomer- ular epithelial stem cells (red) are localized at the urinary pole. A transitional cell unipotent progenitors.33 This feature population (podocyte progenitors, red/light blue) displays features of either glomer- was demonstrated by first culturing ular epithelial stem cells or podocytes (light blue) and localize between the urinary pole progeny derived from single CD24ϩ, ϩ and the vascular stalk. Cells that express only podocyte markers and the phenotypic CD133 cells and then transplanting features of differentiated podocytes localize at the vascular stalk of the glomerulus or them into SCID mice with focal segmen- within the glomerular tuft (light blue). Proposed mechanisms of podocyte regeneration tal glomerulosclerosis (FSGS).33 are depicted in more detail in (A), (B), and (C). (A) Glomerular epithelial stem cells can ϩ ϩ CD24 , CD133 stem cells follow a self-renew and also generate novel podocytes by progressively proliferating and phenotypical and functional hierarchy to differentiating toward the vascular stalk. This occurs as the kidney grows, during generate a population of podocyte-com- childhood and adolescence, and might also occur after an injury, which allows for a mitted progenitors between the urinary slow generation of novel podocytes, such as after uninephrectomy. (B and C) In and the vascular pole of Bowman’s capsule, glomerular disorders characterized by severe podocyte death or detachment, glomer- ular epithelial stem cells generate cell bridges between the Bowman’s capsule and the expressing both stem cells and podocyte glomerular tuft, which may allow a quick replacement of lost podocytes. (B) Cell markers (Figure 1). These progenitors dif- bridges may provide a slide for the migration, proliferation, and differentiation of an ferentiate only toward the podocyte lineage adjacent progenitor and a quick replacement of lost podocytes. (C) Bridging parietal 33 and lack the properties of self-renewal. epithelial cells might also acquire podocyte markers after injury and directly replace the Previous studies show the existence of lost podocytes. The directions of migration, proliferation, and differentiation of glo- transitional cells exhibiting a mixed phe- merular epithelial stem cells to regenerate lost podocytes are indicated by the arrows. notype between parietal epithelial cells and neo-podocytes in proximity of the vascular (Figure 1).38 Genetic labeling also supports podocytes. Indeed, the possibility that pa- stalk of the glomerulus.36,37 Podocyte- the notion that this parietal epithelial cell rietal epithelial cells also migrate from committed progenitors proliferate and dif- population regenerates itself.38 Thus, pari- Bowman’s capsule to the capillary tuft in ferentiate into cells that loose stem cell etal epithelial cells have the ability not only regions different than the vascular pole is markers and acquire high levels of podo- to generate differentiated podocytes but suggested by adhesions and also bridges cyte-specific markers as they progressively also to self-renew, which further demon- representing new migratory tracks be- migrate toward the vascular stalk of the strates they represent stem cells. A contin- tween Bowman’s capsule and the tuft (Fig- Bowman’s capsule (Figure 1).33 These uous generation of novel podocytes occurs ure 1).25,39 Interestingly, a recent study us- findings in humans were also confirmed in as the kidney grows,38 and might also occur ing genetic tagging of parietal epithelial parallel studies performed in rodents. In- during enlargement of a contralateral kid- cells demonstrates that bridges between deed, using genetic tagging of parietal epi- ney after uninephrectomy. Bowman’s capsule and the glomerular tuft thelial cells, Appel et al.38 demonstrated However, in glomerular disorders char- in experimental