Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification

Taketaro Sadahiro, Mari Isomi, Naoto Muraoka, Hidenori Kojima, Sho Haginiwa, Shota Kurotsu, Fumiya Tamura, Hidenori Tani, Shugo Tohyama, Jun Fujita, Hiroyuki Miyoshi, Yoshifumi Kawamura, Naoki Goshima, Yuka W. Iwasaki, Kensaku Murano, Kuniaki Saito, Mayumi Oda, Peter Andersen, Chulan Kwon, Hideki UosakiHirofumi Nishizono, Keiichi Fukuda, Masaki Ieda

Research output: Contribution to journalArticlepeer-review

Abstract

The mesoderm arises from pluripotent epiblasts and differentiates into multiple lineages; however, the underlying molecular mechanisms are unclear. Tbx6 is enriched in the paraxial mesoderm and is implicated in somite formation, but its function in other mesoderms remains elusive. Here, using direct reprogramming-based screening, single-cell RNA-seq in mouse embryos, and directed cardiac differentiation in pluripotent stem cells (PSCs), we demonstrated that Tbx6 induces nascent mesoderm from PSCs and determines cardiovascular and somite lineage specification via its temporal expression. Tbx6 knockout in mouse PSCs using CRISPR/Cas9 technology inhibited mesoderm and cardiovascular differentiation, whereas transient Tbx6 expression induced mesoderm and cardiovascular specification from mouse and human PSCs via direct upregulation of Mesp1, repression of Sox2, and activation of BMP/Nodal/Wnt signaling. Notably, prolonged Tbx6 expression suppressed cardiac differentiation and induced somite lineages, including skeletal muscle and chondrocytes. Thus, Tbx6 is critical for mesoderm induction and subsequent lineage diversification. Sadahiro et al. show that Tbx6 is critical for mesoderm induction and subsequent lineage diversification from pluripotent stem cells (PSCs). Transient Tbx6 expression induced nascent mesoderm and cardiovascular lineages from mouse and human PSCs, whereas prolonged Tbx6 expression suppressed cardiac differentiation and induced somite lineages, including skeletal muscle and chondrocytes.

Original languageEnglish (US)
Pages (from-to)382-395.e5
JournalCell stem cell
Volume23
Issue number3
DOIs
StatePublished - Sep 6 2018

Keywords

  • Tbx6
  • cardiovascular
  • chondrocyte
  • mesoderm
  • pluripotent stem cell
  • skeletal muscle

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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