Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant…

• SO
  Society of General Internal Medicine
• BH
  British Heart Foundation
• EC
  European Commission

  Awards: 101043403, 884754, 101001791, 757339, 677448
• DF
  Deutsche Forschungsgemeinschaft

  Awards: SFBTRR219, 454024652, 432698239, 445703531, CRU344, CRU5011, 322900939
• BF
  Bundesministerium für Bildung und Forschung

  Award: 01KL1907
• NO
  Nederlandse Organisatie voor Wetenschappelijk Onderzoek

  Award: VIDI 09150172010072
• RA
  RWTH Aachen University

  Awards: 139/21, SFBTRR219
• DG
  Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
• S
  Servier
• ER
  European Research Area Network on Cardiovascular Diseases
• H2
  Horizon 2020 Framework Programme
• ER
  European Research Council
• H2
  Horizon 2020

  Award: GA 884754
• HE
  H2020 European Research Council