Cystogenic potential of CD133+ progenitor cells of human polycystic kidneys

Abstract

In autosomal dominant polycystic kidney disease, cysts arise focally and disrupt normal renal tissue leading to renal failure. In the present study, we show that cyst-lining cells express the stem cell marker CD133. CD133+ progenitor cells isolated from polycystic kidney, carrying mutations of PKD genes, showed a dedifferentiated phenotype similar to CD133+ progenitor cells from normal kidney. However, these cells were more proliferative and presented a defective epithelial differentiation phenotype with respect to normal renal CD133+ cells as they were not able to express all tubular epithelial cell markers when cultured in epithelial differentiation medium. Polycystic CD133+ cells, in contrast to normal renal CD133+ cells, formed cysts in vitro in a three-dimensional culture system and in vivo when injected subcutaneously within Matrigel in SCID mice. Rapamycin treatment reduced in vitro proliferation of polycystic CD133+ cells and decreased cystogenesis both in vitro and in vivo. The in vitro epithelial differentiation was only partially improved by rapamycin. These results indicate that polycystic CD133+ cells retain a dedifferentiated phenotype and the ability to generate cysts.

Safety and tolerability of autologous bone marrow mesenchymal stromal cells in ADPKD patients

“…Rapamycin decreases the proliferation of CD133+ and CD24+ cells and cyst formation in vitro through inhibition of the mechanistic target of rapamycin (mTOR) in PKD [17]. In our in vitro study, we observed that MSCs could reduce the proliferative potential and cyst formation of CD133+ progenitor cells from ADPKD patients (unpublished data).…”

“…In a recent study, our results indicated that MSCs resulted in decreased CKD progression in a monkey model [16]. Carvalhosa et al reported that cells lining cysts in ADPKD consisted of polycystic CD133+ progenitor [17]. Our unpublished data showed that in vitro co-culture of MSCs and tubular CD133+ progenitor cells from ADPKD patients resulted in reduced cyst formation and proliferation potential.…”

Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease

“…However, CD133 + progenitor cells from human polycystic kidneys, but not from normal kidneys, form cysts in vitro and in severe combined immunodeficiency mice (33). Rapamycin inhibits CD133 + proliferation in vitro and suppresses CD133 + progenitor cell-induced cystogenesis (33). Although speculative, these findings raise the possibility that rapamycin might suppress select cell populations, with GFR improving before any detectable effect on TKV or "intermediate volume" (36).…”

“…Rapamycin decreases macrophage colony-stimulating factor-dependent macrophage proliferation in a dose-dependent manner (34) and can inhibit macrophage chemotaxis and phagocytosis (35), but alternatively activated macrophages have not been studied specifically. However, CD133 + progenitor cells from human polycystic kidneys, but not from normal kidneys, form cysts in vitro and in severe combined immunodeficiency mice (33). Rapamycin inhibits CD133 + proliferation in vitro and suppresses CD133 + progenitor cell-induced cystogenesis (33).…”

“…The hypothesized functional improvement from changes in such minute cysts would depend on the location of the cysts (renal cortex: less compression of the vasculature, tubules, and glomeruli; medullary collecting ducts: decreased obstruction of multiple upstream nephrons) (10). Another pathway that could affect early cyst formation and initially have little measurable effect on TKV involves cyst-promoting and cystogenic cells (32,33). In a polycystic mouse model, alternatively activated macrophages home to cystic areas and promote cyst growth (32).…”