Conversion of mouse and human fibroblasts into functional spinal motor neurons

Esther Y. Son, Justin K. Ichida, Brian J. Wainger, Jeremy S. Toma, Victor F. Rafuse, Clifford J. Woolf, Kevin Eggan

Research output: Contribution to journalArticlepeer-review

558 Citations (Scopus)

Abstract

The mammalian nervous system comprises many distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although specific neuronal types can be isolated from rodent embryos or engineered from stem cells for translational studies, transcription factor-mediated reprogramming might provide a more direct route to their generation. Here we report that the forced expression of select transcription factors is sufficient to convert mouse and human fibroblasts into induced motor neurons (iMNs). iMNs displayed a morphology, gene expression signature, electrophysiology, synaptic functionality, in vivo engraftment capacity, and sensitivity to degenerative stimuli similar to those of embryo-derived motor neurons. We show that the converting fibroblasts do not transit through a proliferative neural progenitor state, and thus form bona fide motor neurons via a route distinct from embryonic development. Our findings demonstrate that fibroblasts can be converted directly into a specific differentiated and functional neural subtype, the spinal motor neuron.

Original languageEnglish
Pages (from-to)205-218
Number of pages14
JournalCell Stem Cell
Volume9
Issue number3
DOIs
Publication statusPublished - Sept 2 2011

Bibliographical note

Funding Information:
We are grateful to A.C. Carter for help with lineage tracing experiments and E. Kiskinis, S. de Boer, G. Boulting, and J. Rivera-Feliciano for providing reagents and helpful discussions. We would also like to thank B. Tilton for assistance with FACS, K. Harrison for providing the mouse Hb9 cDNA, N. Atwater for assistance with glia preparation, J. Sandoe and K. Sandor for help with molecular cloning, K. Koszka for help with mouse husbandry, and M.Y. Son for help with the diagram in Figure 1. This work was made possible by support provided by the Howard Hughes Medical Institute, the Harvard Stem Cell Institute, P 2 ALS, the New York Stem Cell Foundation, NIH GO grant 1RC2 NS069395-01, and NIH grant R01 HD045732-03 to K.E. J.K.I. is supported by the Novartis Institutes for BioMedical Research and a Stan and Fiona Druckenmiller/New York Stem Cell Foundation postdoctoral fellowship. B.J.W. is supported by NIH Training Grant 5T32GM007592. C.J.W. used facilities provided by the Children's Hospital Boston Intellectual and Developmental Disabilities Research Center and the NIH. J.S.T. was funded by a Natural Sciences and Engineering Research Council of Canada graduate student scholarship award. V.F.R is supported by the Natural Sciences and Engineering Research Council of Canada. The authors are filing a patent based on the results reported in this paper. K.E. is a member of the iPierian scientific advisory board.

ASJC Scopus Subject Areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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Son, E. Y., Ichida, J. K., Wainger, B. J., Toma, J. S., Rafuse, V. F., Woolf, C. J., & Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell, 9(3), 205-218. https://doi.org/10.1016/j.stem.2011.07.014