한빛사 논문
Abstract
Jae-Won Shin1, 2, Amnon Buxboim1, Kyle R. Spinler1, Joe Swift1, David A. Christian3, Christopher A. Hunter3, Catherine Leon4, Christian Gachet4, P.C. Dave P. Dingal1, Irena L. Ivanovska1, Florian Rehfeldt1, Joel Anne Chasis5, 6, Dennis E. Discher1, 2
1 Biophysical Engineering Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
2 Cell and Molecular Biology and Pharmacology Graduate Groups, University of Pennsylvania, Philadelphia, PA 19104, USA
3 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
4 UMR S949, Inserm, Universite de Strasbourg, Etablissement Francais du Sang, Strasbourg, 67000, France
5 Life Sciences Division, University of California, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
6 Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
Corresponding author : Dennis E. Discher
Summary
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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