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  • br Introduction Cell based therapies are emerging as

    2018-10-20


    Introduction Cell-based therapies are emerging as one of the most promising approaches of regenerative medicine (Riazi et al., 2009). In the kidney field, the search for a renal-specific stem cell led to the discovery of progenitor order SCH772984 that protect animals from acute kidney injury (AKI) when systemically infused (Angelotti et al., 2012; Benigni et al., 2010). However, the cell number is a limiting factor, and their biology is far from known. Therefore, other non-renal stem cell sources have been pursued. Derivation of human embryonic stem cells (hESCs) (Thomson et al., 1998) has raised hope because they can give rise to all three germ layers, but progress toward somatic populations has encountered major obstacles, including the risk of cancer and rejection, not to mention the ethical issues involved. The same holds true for induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006), which are similar to hESCs but devoid of at least some of the above problems. The generation of hESC/iPSC-derived mature renal cells (Song et al., 2012) and, more recently, intermediate mesoderm/metanephric mesenchyme (MM) and ureteric bud (UB) renal progenitors (Lam et al., 2014; Lin et al., 2010; Mae et al., 2013; Takasato et al., 2014) has been reported. In principle, patient-specific cells to be used therapeutically could be obtained through reprogramming approaches in which a long-standing interest exists because of the possibility that abundant adult cells can easily be harvested and converted to other cell types (Zhou et al., 2008). In this context, studies have defined sets of transcription factors that can directly reprogram somatic cells into another cell type without passing through the pluripotent state (Ginsberg et al., 2012; Ieda et al., 2010; Karow et al., 2012; Vierbuchen et al., 2010). Using a strategy of re-expressing key developmental regulators in vitro/in vivo, adult cell reprogramming occurs, through which induced cells residing in their native environment might promote their survival and/or maturation (Ginsberg et al., 2012; Ieda et al., 2010; Karow et al., 2012; Qian et al., 2012; Vierbuchen et al., 2010; Zhou et al., 2008). In parallel with these developments, an intriguing technology for direct cell reprogramming by exposing reversibly permeabilized somatic cells to cell-free extracts has emerged. This method has its origins in the early experiments of Briggs and King, followed by Gurdon (Gurdon, 2006), where a somatic cell nucleus was transferred (SCNT [somatic cell nuclear transfer]) to an enucleated oocyte, resulting in the activation of the somatic cell nucleus. Cell-extract reprogramming was first demonstrated with extracts of regenerating newt limbs, which promoted cell-cycle re-entry and downregulation of myogenic markers in differentiated myotubes (McGann et al., 2001). Afterward, this approach yielded in-vitro-reprogrammed somatic cells with the extracts from T cells, cardiomyocytes, insulinoma cells, pneumocytes, chromaffin, or embryonic stem cells (Gaustad et al., 2004; Håkelien et al., 2002, 2004; Landsverk et al., 2002; Qin et al., 2005; Qu et al., 2013; Rajasingh et al., 2008). Surprisingly, there is a paucity of attempts at the reverse reprogramming of adult stem cells toward somatic cells. Human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal stem cells, are adult stem/progenitor cells with self-renewal capacity and restricted potential for generating skeletal tissues, including osteoblast, chondrocyte, adipocyte, and perivascular stromal cells (Bianco et al., 2013; Le Blanc and Mougiakakos, 2012). Whether BMSCs can be used therapeutically is still a matter of debate. Based on their paracrine action rather than differentiation ability, these cells have been used with promising results in different diseases (Le Blanc and Mougiakakos, 2012; Morigi and Benigni, 2013; Reinders et al., 2014; Souidi et al., 2013). No evidence of direct reprogramming of BMSCs into somatic cells is available yet.