title: Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4.
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.
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany.
authors: Hannah
authors: 0000-0003-2048-7357
authors: H
authors: Uckelmann
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany.
authors: Sandra
authors: S
authors: Blaszkiewicz
authors: Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Planegg, Germany.
authors: Claudia
authors: C
authors: Nicolae
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany.
authors: Simon
authors: S
authors: Haas
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany.
authors: Alexandra
authors: A
authors: Schnell
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany.
authors: Stephan
authors: S
authors: Wurzer
authors: Center for Biochemistry, Medical Faculty and Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors: Raimund
authors: R
authors: Wagener
authors: Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Planegg, Germany Department of General, Trauma, Hand, and Plastic Surgery, Ludwig-Maximilians University, 80539 Munich, Germany.
authors: Attila
authors: 0000-0003-3569-6557
authors: A
authors: Aszodi
authors: HSCs and Stress Group, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany Heidelberg Institute for Stem Cell Technologies and Experimental Medicine gGmbH, 69120 Heidelberg, Germany m.essers@dkfz.de.
authors: Marieke Alida Gertruda
authors: MA
authors: Essers
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D064235:Matrilin Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: C577547:Matn4 protein, mouse; D064235:Matrilin Proteins; D019718:Receptors, CXCR4