PMID- 35377804 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20221006 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 119 IP - 15 DP - 2022 Apr 12 TI - Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss. PG - e2111445119 LID - 10.1073/pnas.2111445119 [doi] LID - e2111445119 AB - Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell- and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFbeta1). Blocking TGFbeta signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell-stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration. FAU - Larouche, Jacqueline A AU - Larouche JA AUID- ORCID: 0000-0001-9380-3547 AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. FAU - Fraczek, Paula M AU - Fraczek PM AUID- ORCID: 0000-0002-9897-0720 AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. FAU - Kurpiers, Sarah J AU - Kurpiers SJ AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. FAU - Yang, Benjamin A AU - Yang BA AUID- ORCID: 0000-0001-7412-6261 AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. FAU - Davis, Carol AU - Davis C AUID- ORCID: 0000-0003-3082-8995 AD - Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109. FAU - Castor-Macias, Jesus A AU - Castor-Macias JA AUID- ORCID: 0000-0002-2501-1035 AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. FAU - Sabin, Kaitlyn AU - Sabin K AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. FAU - Anderson, Shannon AU - Anderson S AD - Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332. FAU - Harrer, Julia AU - Harrer J AUID- ORCID: 0000-0003-0878-8659 AD - Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332. FAU - Hall, Matthew AU - Hall M AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. FAU - Brooks, Susan V AU - Brooks SV AUID- ORCID: 0000-0003-1954-967X AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109. FAU - Jang, Young C AU - Jang YC AUID- ORCID: 0000-0002-9489-2104 AD - Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332. AD - School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332. FAU - Willett, Nick AU - Willett N AD - Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR 97403. FAU - Shea, Lonnie D AU - Shea LD AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. FAU - Aguilar, Carlos A AU - Aguilar CA AUID- ORCID: 0000-0003-3830-0634 AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109. AD - Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109. AD - Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109. LA - eng GR - P30 AG024824/AG/NIA NIH HHS/United States GR - P30 AR069620/AR/NIAMS NIH HHS/United States GR - R25 GM086262/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20220404 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Transforming Growth Factor beta) SB - IM MH - Animals MH - Fibrosis MH - *Killer Cells, Natural/immunology MH - Mice MH - *Muscle, Skeletal/immunology/pathology MH - *Muscular Diseases/immunology/pathology MH - Neutrophil Infiltration MH - *Neutrophils/immunology MH - *Regeneration/immunology MH - *Satellite Cells, Skeletal Muscle/immunology MH - Transforming Growth Factor beta/metabolism PMC - PMC9169656 OTO - NOTNLM OT - inflammation OT - muscle stem cells OT - single-cell RNA sequencing OT - skeletal muscle COIS- The authors declare no competing interest. EDAT- 2022/04/05 06:00 MHDA- 2022/04/16 06:00 PMCR- 2022/10/04 CRDT- 2022/04/04 17:10 PHST- 2022/04/04 17:10 [entrez] PHST- 2022/04/05 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2022/10/04 00:00 [pmc-release] AID - 202111445 [pii] AID - 10.1073/pnas.2111445119 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2111445119. doi: 10.1073/pnas.2111445119. Epub 2022 Apr 4.