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Development. 2018 Nov 21;145(22). pii: dev168617. doi: 10.1242/dev.168617.

Comparative genomic analysis of embryonic, lineage-converted and stem cell-derived motor neurons.

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Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Howard Hughes Medical Institute, Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.
Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.


Advances in stem cell science allow the production of different cell types in vitro either through the recapitulation of developmental processes, often termed 'directed differentiation', or the forced expression of lineage-specific transcription factors. Although cells produced by both approaches are increasingly used in translational applications, their quantitative similarity to their primary counterparts remains largely unresolved. To investigate the similarity between in vitro-derived and primary cell types, we harvested and purified mouse spinal motor neurons and compared them with motor neurons produced by transcription factor-mediated lineage conversion of fibroblasts or directed differentiation of pluripotent stem cells. To enable unbiased analysis of these motor neuron types and their cells of origin, we then subjected them to whole transcriptome and DNA methylome analysis by RNA sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). Despite major differences in methodology, lineage conversion and directed differentiation both produce cells that closely approximate the primary motor neuron state. However, we identify differences in Fas signaling, the Hox code and synaptic gene expression between lineage-converted and directed differentiation motor neurons that affect their utility in translational studies.


Directed differentiation; Embryonic stem cells; Lineage conversion; Motor neuron; Reprogramming; iPS cell

[Available on 2019-11-15]

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