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Cell. 2016 Jul 14;166(2):451-467. doi: 10.1016/j.cell.2016.06.011.

Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.

Author information

1
Department of Developmental Biology, Institute for Stem Cell Biology & Regenerative Medicine, Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University School of Medicine, CA 94305, USA.
2
Departments of Genetics and Computer Science, Stanford University School of Medicine, CA 94305, USA.
3
Department of Cell and Developmental Biology, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
5
Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
6
Department of Developmental Biology, Institute for Stem Cell Biology & Regenerative Medicine, Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University School of Medicine, CA 94305, USA; Department of Biochemistry, Howard Hughes Medical Institute, Stanford University School of Medicine, CA 94305, USA.
7
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore. Electronic address: anglt1@gis.a-star.edu.sg.
8
Department of Developmental Biology, Institute for Stem Cell Biology & Regenerative Medicine, Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University School of Medicine, CA 94305, USA. Electronic address: irv@stanford.edu.

Abstract

Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT.

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PMID:
27419872
PMCID:
PMC5474394
[Available on 2017-07-14]
DOI:
10.1016/j.cell.2016.06.011
[Indexed for MEDLINE]
Free PMC Article

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