A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Andreas Patsalos, Laszlo Halasz, Miguel A. Medina-Serpas, Wilhelm K. Berger, Bence Daniel, Petros Tzerpos, Máté Kiss, Gergely Nagy, Cornelius Fischer, Zoltan Simandi, Tamas Varga, Laszlo Nagy

Research output: Contribution to journalArticlepeer-review


Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs]).

Original languageEnglish (US)
Article numbere20210420
JournalJournal of Experimental Medicine
Issue number1
StatePublished - Nov 30 2021

ASJC Scopus subject areas

  • General Medicine


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