Direct comparison of human pluripotent stem cell derivatives with tissue-derived counterparts

by Alexey Bersenev on September 12, 2011

in embryonic/iPS

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Recently William’s Lowry group have assessed human pluripoten stem cell (hPSC) progeny (neural cells, fibroblasts and hepatocytes) and directly compared them with tissue-derived counterparts. This type of experiment was performed for the first time. They got quite intriguing results:

… when compared to a tissue-derived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives.

So, the most important conclusion is that hPSC progeny, despite functional and phenotypic maturation, continue to express (aberrantly) some pluripotency genes and resemble “early embryo” genetic program. But what are the consequences for potential therapeutic application of hPSC? This question was recently discussed in commentary:

It is possible that some malingering undifferentiated hPSCs persisted throughout the differentiation protocols, consequently contributing to the elevated expression of these pluripotency genes in hPSC-derived lineages. Whatever the reason, enduring expression of pluripotency genes in stem cell-derived progeny is translationally troublesome; for example, one notes that expression of LIN28 in differentiated cells is tumorigenic. Might hPSC-derived differentiated cells be prone to oncogenic subversion? If so, this could indeed pose a serious impediment to the exploitation of differentiated derivatives of hPSCs for cell-based therapies in human patients.

The authors pointed out that hPSC “immaturity” could also impact the functionality of their progeny:

What do these findings portend for the usage of hPSCs for regenerative medicine? Are transcriptional incongruences between hPSC-derived and fetal cells causes for concern? One utilitarian argument to be waged is that it is inconsequential that hPSC-derived progeny are transcriptionally divergent from their in vivo counterparts — as long as they can physiologically perform. This also invokes another challenge. The apparent “developmental naïvety” of hPSC-derived cells also remains an important clinical concern — to frame it in the above example of β-cells; adult β-cells secrete insulin in response to glucose, but fetal β-cells do not.

It will be interesting to see the comparison of hPSC progeny with adult but not fetal counterparts. What do you think?

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