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

doi:10.1016/j.stem.2013.10.009

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 journal › Article › peer-review

106 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 language	English
Pages (from-to)	81-93
Number of pages	13
Journal	Cell Stem Cell
Volume	14
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2013.10.009
State	Published - 2 Jan 2014
Externally published	Yes

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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10.1016/j.stem.2013.10.009

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title = "Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells",

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.",

author = "Shin, {Jae Won} and Amnon Buxboim and Spinler, {Kyle R.} and Joe Swift and Christian, {David A.} and Hunter, {Christopher A.} and Catherine L{\'e}on and Christian Gachet and Dingal, {P. C.Dave P.} and Ivanovska, {Irena L.} and Florian Rehfeldt and Chasis, {Joel Anne} and Discher, {Dennis E.}",

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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doi = "10.1016/j.stem.2013.10.009",

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T1 - Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells

AU - Shin, Jae Won

AU - Buxboim, Amnon

AU - Spinler, Kyle R.

AU - Swift, Joe

AU - Christian, David A.

AU - Hunter, Christopher A.

AU - Léon, Catherine

AU - Gachet, Christian

AU - Dingal, P. C.Dave P.

AU - Ivanovska, Irena L.

AU - Rehfeldt, Florian

AU - Chasis, Joel Anne

AU - Discher, Dennis E.

N1 - 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.).

PY - 2014/1/2

Y1 - 2014/1/2

N2 - 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.

AB - 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.

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SN - 1934-5909

VL - 14

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JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -

Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells

Abstract

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