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Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4

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Item Type:Article
Title:Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4
Creators Name:Uckelmann, H., Blaszkiewicz, S., Nicolae, C., Haas, S., Schnell, A., Wurzer, S., Wagener, R., Aszodi, A. and Essers, M.A.G.
Abstract:During homeostasis, hematopoietic stem cells (HSCs) are mostly kept in quiescence with only minor contribution to steady-state hematopoiesis. However, in stress situations such as infection, chemotherapy, or transplantation, HSCs are forced to proliferate and rapidly regenerate compromised hematopoietic cells. Little is known about the processes regulating this stress-induced proliferation and expansion of HSCs and progenitors. In this study, we identified the extracellular matrix (ECM) adaptor protein Matrilin-4 (Matn4) as an important negative regulator of the HSC stress response. Matn4 is highly expressed in long-term HSCs; however, it is not required for HSC maintenance under homeostasis. In contrast, Matn4 is strongly down-regulated in HSCs in response to proliferative stress, and Matn4 deficiency results in increased proliferation and expansion of HSCs and progenitors after myelosuppressive chemotherapy, inflammatory stress, and transplantation. This enhanced proliferation is mediated by a transient down-regulation of CXCR4 in Matn4(-/-) HSCs upon stress, allowing for a more efficient expansion of HSCs. Thus, we have uncovered a novel link between the ECM protein Matn4 and cytokine receptor CXCR4 involved in the regulation of HSC proliferation and expansion under acute stress.
Keywords:Bone Marrow Transplantation, Cell Proliferation, CXCR4 Receptors, Down-Regulation, Hematopoiesis, Hematopoietic Stem Cells, Inbred C57BL Mice, Matrilin Proteins, Physiological Stress, Animals, Mice
Source:Journal of Experimental Medicine
ISSN:0022-1007
Publisher:Rockefeller University Press
Volume:213
Number:10
Page Range:1961-1971
Date:19 September 2016
Official Publication:https://doi.org/10.1084/jem.20151713
PubMed:View item in PubMed

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