Extracellular matrix protein Matrilin-4 regulates stressinduced HSC proliferation via CXCR4

Hannah Uckelmann, Sandra Blaszkiewicz, Claudia Nicolae, Simon Haas, Alexandra Schnell, Stephan Wurzer, Raimund Wagener, Attila Aszodi, Marieke Alida Gertruda Essers

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


During homeostasis, hematopoietic stem cells (HSCs) are mostly kept in quiescence with only minor contribution to steadystate 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.

Original languageEnglish (US)
Pages (from-to)1961-1971
Number of pages11
JournalJournal of Experimental Medicine
Issue number10
StatePublished - Sep 19 2016

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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