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      Therapeutic use of human renal progenitor cells for kidney regeneration

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      Nature Reviews Nephrology

      Springer Science and Business Media LLC

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          Abstract

          The ability of the human kidney to repair itself is limited. Consequently, repeated injury can trigger a maladaptive response that is characterized by fibrosis and loss of renal function. The transcription patterns that characterize nephrogenesis in fetal renal progenitor cells (RPCs) are only partially activated during renal repair in adults. Nevertheless, evidence suggests that segment-restricted progenitor resident cells support renal healing in adults. In this Review, we discuss the evidence for the existence of functional human RPCs in adults and their role in renal repair, and consider the controversial issue of whether RPCs are a fixed population or arise through phenotypical plasticity of tubular cells that is mediated by the microenvironment. We also discuss the strategies for generating renal progenitor cells from pluripotent stem cells or differentiated cells and their use in therapy. Finally, we examine preclinical data on the therapeutic use of human fetal cells, adult progenitor cells and adult renal cells.

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          Most cited references 80

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          Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

          Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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            Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells.

            Recapitulating three-dimensional (3D) structures of complex organs, such as the kidney, from pluripotent stem cells (PSCs) is a major challenge. Here, we define the developmental origins of the metanephric mesenchyme (MM), which generates most kidney components. Unexpectedly, we find that posteriorly located T(+) MM precursors are developmentally distinct from Osr1(+) ureteric bud progenitors during the postgastrulation stage, and we identify phasic Wnt stimulation and stage-specific growth factor addition as molecular cues that promote their development into the MM. We then use this information to derive MM from PSCs. These progenitors reconstitute the 3D structures of the kidney in vitro, including glomeruli with podocytes and renal tubules with proximal and distal regions and clear lumina. Furthermore, the glomeruli are efficiently vascularized upon transplantation. Thus, by reevaluating the developmental origins of metanephric progenitors, we have provided key insights into kidney specification in vivo and taken important steps toward kidney organogenesis in vitro. Copyright © 2014 Elsevier Inc. All rights reserved.
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              WT-1 is required for early kidney development.

              In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital development.
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                Author and article information

                Journal
                Nature Reviews Nephrology
                Nat Rev Nephrol
                Springer Science and Business Media LLC
                1759-5061
                1759-507X
                December 2015
                August 4 2015
                December 2015
                : 11
                : 12
                : 695-706
                Article
                10.1038/nrneph.2015.126
                26241019
                © 2015

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