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Contributed by Rudolf Jaenisch, December 30, 2015 (sent for review December 6, 2015; reviewed by Nissim Benvenisty and Juan Carlos Izpisua Belmonte)
Significance
We generated mouse–human neural crest chimeras by introducing neural crest cells derived from human embryonic stem cells or induced pluripotent stem cells (iPSCs) in utero into the gastrulating mouse embryo. The cells migrated in the embryo along normal migration routes and contributed to functional pigment cells in the postnatal animal, as demonstrated by coat color contribution. This experimental system represents a novel paradigm that allows studying the developmental potential of human cells under in vivo conditions. Importantly, this platform will allow for the investigation of human diseases in the animal by using patient-derived iPSCs.
Abstract
The neural crest (NC) represents multipotent cells that arise at the interphase between ectoderm and prospective epidermis of the neurulating embryo. The NC has major clinical relevance because it is involved in both inherited and acquired developmental abnormalities. The aim of this study was to establish an experimental platform that would allow for the integration of human NC cells (hNCCs) into the gastrulating mouse embryo. NCCs were derived from pluripotent mouse, rat, and human cells and microinjected into embryonic-day-8.5 embryos. To facilitate integration of the NCCs, we used recipient embryos that carried a c-Kit mutation (Wsh/Wsh), which leads to a loss of melanoblasts and thus eliminates competition from the endogenous host cells. The donor NCCs migrated along the dorsolateral migration routes in the recipient embryos. Postnatal mice derived from injected embryos displayed pigmented hair, demonstrating differentiation of the NCCs into functional melanocytes. Although the contribution of human cells to pigmentation in the host was lower than that of mouse or rat donor cells, our results indicate that hNCCs, injected in utero, can integrate into the embryo and form mature functional cells in the animal. This mouse–human chimeric platform allows for a new approach to study NC development and diseases.
Footnotes
↵1Present address: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
- ↵2To whom correspondence should be addressed. Email: jaenisch{at}wi.mit.edu.
Author contributions: M.A.C. and R.J. designed research; M.A.C. performed research; K.J.W., J.G., S.M., Y.B., and D.F. contributed new reagents/analytic tools; M.A.C. and K.J.W. analyzed data; and M.A.C., K.J.W., and R.J. wrote the paper.
Reviewers: N.B., The Hebrew University of Jerusalem; and J.C.I.B., The Salk Institute for Biological Studies.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1525518113/-/DCSupplemental.
http://www.pnas.org/preview_site/misc/userlicense.xhtml
Human NCCs contribute to interspecies chimeras
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