Regeneration of Glomerular Podocytes by Human Renal Progenitors

Abstract

Depletion of podocytes, common to glomerular diseases in general, plays a role in the pathogenesis of glomerulosclerosis. Whether podocyte injury in adulthood can be repaired has not been established. Here, we demonstrate that in the adult human kidney, CD133ϩCD24ϩ cells consist of a hierarchical population of progenitors that are arranged in a precise sequence within Bowman's capsule and exhibit heterogeneous potential for differentiation and regeneration. Cells localized to the urinary pole that expressed CD133 and CD24, but not podocyte markers (CD133ϩCD24ϩPDXϪ cells), could regenerate both tubular cells and podocytes. In contrast, cells localized between the urinary pole and vascular pole that expressed both progenitor and podocytes markers (CD133ϩCD24ϩPDXϩ) could regenerate only podocytes. Finally, cells localized to the vascular pole did not exhibit progenitor markers, but displayed phenotypic features of differentiated podocytes (CD133ϪCD24ϪPDXϩ cells). Injection of CD133ϩCD24ϩPDXϪ cells, but not CD133ϩCD24ϩPDXϩ or CD133-CD24Ϫ cells, into mice with adriamycin-induced nephropathy reduced proteinuria and improved chronic glomerular damage, suggesting that CD133ϩCD24ϩPDXϪ cells could potentially treat glomerular disorders characterized by podocyte injury, proteinuria, and progressive glomerulosclerosis. Glomerular diseases account for 90% of ESRD at a cost of $20 billion/yr in the United States. 1 The traditional glomerular disease classification encompasses a bewildering array of descriptive pathologic entities and their clinical counterparts. However, converging evidence suggests that podocyte depletion, secondary to toxic, genetic, immune, infectious, oxidant, metabolic, hemodynamic, and other mechanisms, is a common determining factor that can result in a broad spectrum of clinical syndromes. As long as the podocyte loss is limited, restitution or repair is possible. By contrast, 20 to 40% podocyte loss results in a scarring response, until at greater than 60% podocyte loss glomeruli become globally sclerotic and nonfiltering. These stages of podocyte depletion are accompanied by corresponding degrees of proteinuria and, as an increasing proportion of glomeruli become involved, by measurable reduction in the clearance function of the kidney. [1][2][3] To what extent podocytes can be replaced at all during adult life, and if so, how and at what rate, is still unclear. Indeed, mature podocytes have limited capacity to divide in situ and display all phenotypic and functional features of highly spe-

Characterization of Renal Progenitors Committed Toward Tubular Lineage and Their Regenerative Potential in Renal Tubular Injury

“…Clones were generated from CD133þCD24þCD106þ and CD133þCD24þCD106À cells by limiting dilution in 96-well plates in EGM-MV 20% FBS and renal epithelial cell growth medium (REGM) 10% FBS, respectively. Tubulogenic and podocyte differentiations were obtained as previously described [7,17]. Assessment of cell viability following treatment with hemoglobin (0.1-0.5-1 mg/ml) was performed using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay (Promega, Madison, WI, www.promega.com).…”

“…However, whether these regenerating cells derive from differentiated tubular cells or from a subset of renal stem/progenitor cells localized within the nephron remains unknown. In other adult organs, resident stem cell compartments critically participate in regeneration [5,6], and several studies support the existence of a stem/progenitor cell compartment also in adult mammalian kidney [7][8][9][10][11][12][13][14][15][16][17]. Renal progenitors were first identified in humans, where they are characterized by coexpression of two markers, CD133 and CD24 [7][8][9][10][11][12][13][14].…”

“…Renal progenitors were first identified in humans, where they are characterized by coexpression of two markers, CD133 and CD24 [7][8][9][10][11][12][13][14]. CD133þCD24þ human renal progenitors are localized at the urinary pole of Bowman's capsule [7][8][9][10][11][12][13][14] and are capable of podocyte and tubular differentiation [7][8][9][10]17]. However, the tubular portion of the nephron is very long, which suggests that the stem cell compartment localized at the urinary pole of Bowman's capsule may not be unique and that other progenitors may localize along the tubular part of the M.L.A., E.R., L.B., B.M., A.P., C.S., E.P., M.R., and E.L.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; M.G.…”

Podocyte Mitosis – A Catastrophe

“…These results cannot simply be explained through the protective effects of angiotensin converting enzyme inhibitors on podocyte loss, but rather suggest that novel podocytes can potentially be generated. Recently, it was demonstrated that a population of progenitor cells in the parietal epithelium of the Bowman’s capsule of adult human kidney acts as a source of intra-renal progenitors for podocytes [105, 106]. These cells follow a phenotypical and functional hierarchy within the parietal epithelium of Bowman’s capsule.…”

“…These cells follow a phenotypical and functional hierarchy within the parietal epithelium of Bowman’s capsule. A population of renal progenitors committed towards becoming podocytes [106, 107] can be observed at the vascular pole. The existence of transitional cells, exhibiting a mixed phenotype between parietal epithelial cells and neo-podocytes in proximity of the vascular stalk of the glomerulus, has been reported also in other previous studies [108].…”