title: Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.
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.
authors.affiliation: 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.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Loh
authors.affiliation: 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Chen
authors.affiliation: Departments of Genetics and Computer Science, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Pang Wei
authors.initials: PW
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Tianda Z
authors.initials: TZ
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sinha
authors.affiliation: 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.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Amira A
authors.initials: AA
authors.lastname: Barkal
authors.affiliation: 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.
authors.forename: Kimberle Y
authors.initials: KY
authors.lastname: Shen
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jain
authors.affiliation: 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.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Morganti
authors.affiliation: Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.affiliation: 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.
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Fernhoff
authors.affiliation: 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.
authors.forename: Benson M
authors.initials: BM
authors.lastname: George
authors.affiliation: Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Wernig
authors.affiliation: 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.
authors.forename: Rachel E A
authors.initials: REA
authors.lastname: Salomon
authors.affiliation: 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.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Departments of Genetics and Computer Science, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Anshul
authors.initials: A
authors.lastname: Kundaje
authors.affiliation: 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.
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
authors.affiliation: 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.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.affiliation: Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore. Electronic address: anglt1@gis.a-star.edu.sg.
authors.forename: Lay Teng
authors.initials: LT
authors.lastname: Ang
authors.affiliation: 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.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D006321:Heart / Q000254:growth & development; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism; D054240:Primitive Streak / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D059010:Single-Cell Analysis; D019170:Somites / Q000378:metabolism; D013234:Stem Cells; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C476884:HOPX protein, human; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins