The Development of Macrophage-Mediated Cell Therapy to Improve Skeletal Muscle Function after Injury.

Viktoriya Rybalko,Roger P Farrar,Melissa Merscham-Banda,Pei-Ling Hsieh,Laura J Suggs,Antonio Musaro

doi:10.1371/journal.pone.0145550

Viktoriya Rybalko, Roger P Farrar + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0145550

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Journal: PloS one	Publication Date: Dec 30, 2015
Citations: 54	License type: CC BY 4.0

Affiliation: The University of Texas at Austin

Abstract

Skeletal muscle regeneration following acute injury is a multi-step process involving complex changes in tissue microenvironment. Macrophages (MPs) are one of the key cell types involved in orchestration and modulation of the repair process. Multiple studies highlight the essential role of MPs in the control of the myogenic program and inflammatory response during skeletal muscle regeneration. A variety of MP phenotypes have been identified and characterized in vitro as well as in vivo. As such, MPs hold great promise for cell-based therapies in the field of regenerative medicine. In this study we used bone-marrow derived in vitro LPS/IFN-y-induced M1 MPs to enhance functional muscle recovery after tourniquet-induced ischemia/reperfusion injury (TK-I/R). We detected a 15% improvement in specific tension and force normalized to mass after M1 (LPS/IFN-γ) MP transplantation 24 hours post-reperfusion. Interestingly, we found that M0 bone marrow-derived unpolarized MPs significantly impaired muscle function highlighting the complexity of temporally coordinated skeletal muscle regenerative program. Furthermore, we show that delivery of M1 (LPS/IFN-γ) MPs early in regeneration accelerates myofiber repair, decreases fibrotic tissue deposition and increases whole muscle IGF-I expression.

Highlights

Skeletal muscle regeneration is a multi-step process involving multiple cell types and complex regulatory interactions [1, 2]
Polarization with LPS and IFN-γ induced highly inflammatory cells. The purpose of this experiment was to compare the activation status of differentially polarized MPs treated with lipopolysaccharide (LPS)/Type-I interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)/IFN-γ combinations
Typical toll-like receptor ligand (TLR) ligand such as LPS can induce the transcription of TNF-α as well as IFN-β providing both signals and overcoming the “two signal” requirement [23, 43]

Summary

Introduction

Skeletal muscle regeneration is a multi-step process involving multiple cell types and complex regulatory interactions [1, 2]. Inflammatory cascades following acute injury need to be properly managed in order for the repair to take place. Unresolved inflammatory response may lead to persistent tissue damage by immune cells or collagen deposition [3]. The severity of the inflammatory response largely depends on the type, location and extent of injury. Tourniquetinduced ischemia-reperfusion (TK-I/R) injury affects large areas of the skeletal muscle causing extensive tissue necrosis, prolonged inflammatory response and delayed recovery of muscle force and function [4, 5]. Tourniquets (TK) are used in clinic for plastic, reconstructive and PLOS ONE | DOI:10.1371/journal.pone.0145550. Tourniquets (TK) are used in clinic for plastic, reconstructive and PLOS ONE | DOI:10.1371/journal.pone.0145550 December 30, 2015

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