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| Item Type: | Article |
|---|---|
| Title: | Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4 |
| Creators Name: | Uckelmann, H. and Blaszkiewicz, S. and Nicolae, C. and Haas, S. and Schnell, A. and Wurzer, S. and Wagener, R. and 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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