Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss

• Type of Material: Article
• Authors: Jacqueline A Larouche, University of Michigan; Paula M Fraczek, University of Michigan; Sarah J Kurpiers, University of Michigan; Benjamin A Yang, University of Michigan; Carol Davis, University of Michigan; Jesus A Castor-Macias, University of Michigan; Kaitlyn Sabin, University of Michigan; Shannon Anderson, Georgia Institute of Technology; Julia Harrer, Georgia Institute of Technology; Matthew Hall, University of Michigan; Susan V. Brooks, University of Michigan; Young Jang, Emory University; Nick Willett, Emory University; Lonnie D Shea, University of Michigan; Carlos A Aguilar, University of Michigan
• Language: English
• Date: 2022-04-12
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: © 2022 the Author(s). Published by PNAS.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2111445119
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 119
• Issue: 15
• Start Page: e2111445119
• End Page: e2111445119
• Keywords: inflammation; NK CELLS; Multidisciplinary Sciences; SKELETAL-MUSCLE; INJURY; Science & Technology; single-cell RNA sequencing; INFLAMMATION; FIBROSIS; INTERCELLULAR COMMUNICATION; DYSTROPHIC MUSCLE; MATRIX METALLOPROTEINASES; skeletal muscle; muscle stem cells; Science & Technology - Other Topics; GROWTH-FACTOR-BETA; MACROPHAGE ACTIVATION
• Research Categories: Engineering, Biomedical; Biology, General

Abstract

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 (TGFβ1). Blocking TGFβ 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.