Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133(+) progenitors through Oct4/miR-145 balance

Dept. of Internal Medicine, Center for Molecular Biotechnology, Univ. of Torino, Cso Dogliotti 14, 10126 Torino, Italy.
AJP Renal Physiology (Impact Factor: 3.25). 09/2011; 302(1):F116-28. DOI: 10.1152/ajprenal.00184.2011
Source: PubMed


Low-oxygen tension is an important component of the stem cell microenvironment. In rodents, renal resident stem cells have been described in the papilla, a relatively hypoxic region of the kidney. In the present study, we found that CD133(+) cells, previously described as renal progenitors in the human cortex, were enriched in the renal inner medulla and localized within the Henle's loop and thin limb segments. Once isolated, the CD133(+) cell population expressed renal embryonic and stem-related transcription factors and was able to differentiate into mature renal epithelial cells. When injected subcutaneously in immunodeficient mice within Matrigel, CD133(+) cells generated canalized structures positive for renal specific markers of different nephron segments. Oct4A levels and differentiation potential of papillary CD133(+) cells were higher than those of CD133(+) cells from cortical tubuli. Hypoxia was able to promote the undifferentiated phenotype of CD133(+) progenitors from papilla. Hypoxia stimulated clonogenicity, proliferation, vascular endothelial growth factor synthesis, and expression of CD133 that were in turn reduced by epithelial differentiation with parallel HIF-1α downregulation. In addition, hypoxia downregulated microRNA-145 and promoted the synthesis of Oct4A. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. MicroRNA-145 overexpression in CD133(+) cells induced downrelation of Oct4A at the protein level, inhibited cell proliferation, and stimulated terminal differentiation. This study underlines the role of the hypoxic microenvironment in controlling the proliferation and maintaining a progenitor phenotype and stem/progenitor properties of CD133(+) cells of the nephron. This mechanism may be at the basis of the maintenance of a CD133(+) population in the papillary region and may be involved in renal regeneration after injury.

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    • "Intrinsic mechanisms of tissue repair and regeneration occur in the mammalian kidney to re-acquire functionality after ischemic, toxic or inflammatory insults [9]. Recent evidence indicates that cells with characteristics of progenitors, expressing the stem cell marker CD133 and lacking differentiation markers, are present in different segments of the human nephron, being localized in the Bowman capsule of glomeruli, in proximal tubules as well as in inner medullary papilla region including Henle’s loop and S3 limb segment [10]–[12]. In addition, CD133+ cells in the cortex increase in number after acute renal damage, suggesting their role in renal repair after injury [13]. "
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    ABSTRACT: Extracellular vesicles (EVs) present in the urine are mainly released from cells of the nephron and can therefore provide information on kidney function. We here evaluated the presence of vesicles expressing the progenitor marker CD133 in the urine of normal subjects and of patients undergoing renal transplant. We found that EV expressing CD133 were present in the urine of normal subjects, but not of patients with end stage renal disease. The first day after transplant, urinary CD133+ EVs were present at low levels, to increase thereafter (at day 7). Urinary CD133+ EVs significantly increased in patients with slow graft function in respect to those with early graft function. In patients with a severe pre-transplant vascular damage of the graft, CD133+ EVs did not increase at day 7. At variance, the levels of EVs expressing the renal exosomal marker CD24 did not vary in the urine of patients with end stage renal disease or in transplanted patients in respect to controls. Sorted CD133+ EVs were found to express glomerular and proximal tubular markers. These data indicate that urinary CD133+ EVs are continuously released during the homeostatic turnover of the nephron and may provide information on its function or regenerative potential.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "This is also suggested by the lack of acquirement of epithelial or endothelial markers. Although further studies are required to analyze the possible integration of CD133 + cells from inner medulla in the murine kidney and their differentiation at later time, these results may suggest that these cells display differential properties with respect to those from cortex, as previously described (Bussolati et al. 2012). Indeed, CD133 + cells from the inner medulla were shown in vitro to be responsible for erythropoietin production (Bussolati et al. 2013). "
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    ABSTRACT: Recent approaches of regenerative medicine can offer a therapeutic option for patients undergoing acute kidney injury. In particular, mesenchymal stem cells were shown to ameliorate renal function and recovery after acute damage. We here evaluated the protective effect and localization of CD133+ renal progenitors from the human inner medulla in a model of glycerol-induced acute tubular damage and we compared the results with those obtained with bone marrow-derived mesenchymal stem cells. We found that CD133+ progenitor cells promoted the recovery of renal function, preventing tubular cell necrosis and stimulating resident cell proliferation and survival, similar to mesenchymal stem cells. In addition, by optical imaging analysis, CD133+ progenitor cells accumulated within the renal tissue, and a reduced entrapment in lung, spleen, and liver was observed. Mesenchymal stem cells were detectable at similar levels in the renal tissue, but a higher signal was present in extrarenal organs. Both cell types produced several cytokines/growth factors, suggesting that a combination of different mediators is involved in their biological action. These results indicate that human CD133+ progenitor cells are renotropic and able to improve renal regeneration in acute kidney injury.
    Full-text · Article · May 2014
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    • "By FACS analysis, after indirect staining of freshly isolated adult renal cells, it is possible to notice that a low percentage of CD133 +/CD24 − events have been detected. In addition, Bussolati et al. (2012) (Fig. 3A) show a consistent amount of CD133 +/CD24 − events by FACS analysis on CD133+ cultured renal cells after direct staining. "

    Full-text · Article · Jan 2014 · Stem Cell Research
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