Stem cell-derived renal cells

STEM CELL-DERIVED RENAL CELLS AND PREDICTIVE RENAL IN VITRO MODELS... 

A race on the generation of stem cell-derived renal cells started in 2013. In January 2013 a protocol for the differentiation of hiPSC or hESC into IM was published (Mae et al., 2013). Odd-skipped related (OSR)l was used as the main IM marker, and up to 90% OSRO cells were obtained. More differentiated renal cell types were only obtained at low frequency, which was not sufficient for use of these cells in any application, including in vitro toxicology (Mae et al., 2013). However, briefly afterward the first protocol for the differentiation of human pluripotent stem cells (hPSC) into mature renal cells was published (Narayanan et al., 2013). This protocol was based on hESC, and the differentiated hESC-derived cells exhibited many features of HPTC and were therefore called HPTC-like cells. The hESC-derived HPTC-like cells were then directly used for the development of the first stem cell-based renal in vitro model for the prediction of DIN (Li et al., 2014). (This in vitro model will be described in more detail in the following.) Later in 2013 the race on the generation of stem cell-derived renal cells continued and various alternative protocols were developed (Lam et al., 2014 Xia et al., 2013 Kang and Han, 2014 Taguchi et al., 2014 Takasato et al., 2014) (Fig. 23.1). 

Therefore, differences between properties of PTC in vivo in the normal adult kidney and in vitro properties of PTC and stem cell-derived proximal tubular-like cells may not just reflect dedifferentiation or lack of full terminal differentiation. Rather, altered marker expression patterns seem to be related to the biology of these cells and their response to altered conditions. It is important to keep in mind that human and animal PTC are probably always different under in vitro conditions (compared to the in vivo situation), unless the in vivo simation can be exactly mimicked. This is also important with respect to the interpretation of the differentiation status of stem cell-derived proximal tubular-like cells, as the expression of progenitor markers and markers specific for other renal cell types is normal under in vitro conditions, also in HPTC. For practical reasons we suggest to always compare stem cell-derived cells carefully to respective primary cells cultivated in vitro, which gives a realistic impression of the best possible differentiation state that can be achieved under the conditions used. In addition, rigorous functional tests (e.g., of transporter functions) are often more informative than marker expression patterns in terms of the applicability of stem cell-derived cells for drug screening. 

Li Y, Kandasamy K, Chuah JKC, Lam YN, Toh WS, Oo ZY, Zink D. 2014. Identification of nephrotoxic compounds with embryonic stem cell-derived human renal proximal tubular-like cells. Mol Pharm 11(7) 1982-1990. 

Vigneau C, Polgar K, Striker G, Elliott J, Hyink D, Weber O, Fehling HJ, Keller G, Burrow C, Wilson P. 2007. Mouse embryonic stem cell-derived embryoid bodies generate progenitors that integrate long term into renal proximal tubules in vivo. JAm Soc Nephrol 18(6) 1709 1720. 

A major potential flaw in the future development and therapeutic use of HuCNS-SCs is the risk of immune rejection because the stem cells are derived from fetal donors. This risk has not been addressed in the studies reported to date relating to the use of HuCNS-SCs. Allografts require immunosuppressive treatments, such as cyclosporine, to prevent host rejection. These treatments are not very well tolerated by patients, producing side effects such as renal dysfunction, tremor and hypertension. This may well affect the potential benefits of HuCNS-SC therapy. 

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