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Pluripotency of Human Stem Cells Confirmed

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Review of “Human-Mouse Chimerism Validates Human Stem Cell Pluripotency” from Cell Stem Cell by Stuart P. Atkinson

The ability to form embryonic chimeras and contribute to the developing organism after mouse blastocyst injection represents the gold standard as the most stringent test of the in vivo pluripotency of pluripotent stem cells [1, 2]. Mouse (m)PSCs have previously passed this test, although human (h)PSCs have not, and so some questions on hPSC utility and safety still remain.

Victoria L. Mascetti and Roger A. Pedersen thought that the inability of hPSCs to form chimeras may be due to a developmental stage mismatch between the cells and the developing embryo. Where mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) resemble the cells of the inner cell mass (ICM), known to exist in the “naïve” state, human ESCs and iPSCs resemble a later, more restricted epithelial stem cell state, known as the “primed” state [3]. So if mPSCs can integrate into the blastocyst-stage embryo where the ICM exists, can hPSCs prove themselves to be pluripotent by integrating into a more developed embryo ?

In their new paper, published in Cell Stem Cell [4], the authors found that both hESCs and hiPSCs could efficiently form chimeras when injected into stage-matched gastrulating mouse embryos, but NOT when injected into the earlier blastocyst-stage embryos. Cell tracking found that injected hPSCs, mimicking the embryo’s own cells, migrated and differentiated into cells representative of the three germ layers (endoderm, mesoderm, and ectoderm) so functionally validating the in vivo pluripotency of hPSCs. Importantly, the injected hPSCs did not form teratomas during the time studied.

This stage-matching strategy now suggests that hPSCs are indeed fully pluripotent, safe, and can incorporate and develop normally in the developing embryo, hence are likely to be an important resource for regenerative/reparative therapies. But perhaps the most important aspect of this study is that the ability of hPSCs to form chimeras may help us to study the early stages of human development in an ethically acceptable way.

References

  1. Bradley A, Evans M, Kaufman MH, et al. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 1984;309:255-256.
  2. Nagy A, Rossant J, Nagy R, et al. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 1993;90:8424-8428.
  3. Mascetti VL and Pedersen RA Naivete of the human pluripotent stem cell. Nat Biotechnol 2014;32:68-70.
  4. Mascetti VL and Pedersen RA Human-Mouse Chimerism Validates Human Stem Cell Pluripotency. Cell Stem Cell 2016;18:67-72.