Outside-in integrin signaling regulates hematopoietic stem cells function
Outside-in integrin signaling regulates hematopoietic stem cells function
Integrins play an important role in haematopoietic stem cell (HSC) maintenance in the bone marrow niche. Here, we demonstrate that Periostin (Postn) via interaction with Integrin-αv (Itgav) regulates HSC proliferation. Systemic deletion of Postn results in peripheral blood (PB) anaemia, myelomonocytosis and lymphopenia, while the number of phenotypic HSCs increases in the bone marrow. Postn-/- mice recover faster from radiation injury with concomitant loss of primitive HSCs. HSCs from Postn-/- mice show accumulation of DNA damage generally associated with aged HSCs. Itgav deletion in the haematopoietic system leads to a similar PB phenotype and HSC-intrinsic repopulation defects. Unaffected by Postn, Vav-Itgav-/- HSCs proliferate faster in vitro, illustrating the importance of Postn-Itgav interaction. Finally, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, leading to increase in p27Kip1 expression resulting in improved maintenance of quiescent HSCs. Together, we demonstrate a role for Itgav-mediated outside-in signalling in regulation of HSC proliferation and stemness.
sponsorship: The work was supported by an FWO grant (1.2.665.11.N.00) to S Khurana; FWO grants (G085111N10; G0D1715N), BELSP DEV-REPAIR grant, Odysseus funding, CoE-SCIL, PF03 and GOA/11/012 funding from KU Leuven, and the Balcaen fund, Steverlynck fund and Vanwayenberghe fund to CM Verfaillie. Currently, S Khurana is supported by the Indian Institute of Science Education and Research, Thiruvananthapuram. We thank Prof Dominique Bonnet, Prof Louise Purton and Prof Christa Maes for critical review of the manuscript. (FWO|1.2.665.11.N.00, FWO|G085111N10, FWO|G0D1715N, BELSP DEV-REPAIR grant, Odysseus, CoE-SCIL, KU Leuven|GOA/11/012, KU Leuven|PF03, Balcaen fund, Steverlynck fund, Vanwayenberghe fund, Indian Institute of Science Education and Research, Thiruvananthapuram)
- KU Leuven Belgium
EXPRESSION, Bone Marrow Cells, Models, Biological, PATHWAY, Mice, Phosphatidylinositol 3-Kinases, Animals, Myeloid Cells, BONE-MARROW NICHE, CANCER CELLS, Cells, Cultured, Cell Proliferation, Phosphoinositide-3 Kinase Inhibitors, Science & Technology, ALPHA-V INTEGRINS, Integrases, KINASE INHIBITOR P27(KIP1), Integrin alphaV, Hematopoietic Stem Cells, Multidisciplinary Sciences, SELF-RENEWAL, DNA-DAMAGE, PROGENITOR CELLS, Science & Technology - Other Topics, ADHESION RECEPTORS, Cell Adhesion Molecules, Proto-Oncogene Proteins c-akt, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Protein Binding, Signal Transduction
EXPRESSION, Bone Marrow Cells, Models, Biological, PATHWAY, Mice, Phosphatidylinositol 3-Kinases, Animals, Myeloid Cells, BONE-MARROW NICHE, CANCER CELLS, Cells, Cultured, Cell Proliferation, Phosphoinositide-3 Kinase Inhibitors, Science & Technology, ALPHA-V INTEGRINS, Integrases, KINASE INHIBITOR P27(KIP1), Integrin alphaV, Hematopoietic Stem Cells, Multidisciplinary Sciences, SELF-RENEWAL, DNA-DAMAGE, PROGENITOR CELLS, Science & Technology - Other Topics, ADHESION RECEPTORS, Cell Adhesion Molecules, Proto-Oncogene Proteins c-akt, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Protein Binding, Signal Transduction
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