Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells

Jae Won Shin, Amnon Buxboim, Kyle R. Spinler, Joe Swift, David A. Christian, Christopher A. Hunter, Catherine Léon, Christian Gachet, P. C.Dave P. Dingal, Irena L. Ivanovska, Florian Rehfeldt, Joel Anne Chasis, Dennis E. Discher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated by dephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix, but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed in vivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus a multifunctional node in polarized division and niche sensing.

Original languageAmerican English
Pages (from-to)81-93
Number of pages13
JournalCell Stem Cell
Volume14
Issue number1
DOIs
StatePublished - 2 Jan 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Robert Adelstein, Dr. Mary Anne Conti (NIH-NHLBI), and Dr. Leonard Zon (Harvard) for invaluable comments. We gratefully acknowledge Arielle Glatman Zaretsky for technical assistance in mouse BM transplantation and the Stem Cell Xenograft Core at the University of Pennsylvania, A. Secreto, J. Glover, and Dr. G. Danet-Desnoyers for cells and engraftment studies. This study was supported by the National Institutes of Health (P01DK032094; R01HL062352; R01-EB007049; P30-DK090969; NCATS-8UL1TR000003), the Human Frontier Science Program (I.I. and D.E.D.), the National Science Foundation (D.E.D.), the Nano Science and Engineering Center-Nano Bio Interface Center (D.E.D.), and the American Heart Association (J.-W.S.).

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