Partial Ablation of Non-Myogenic Progenitor Cells as a Therapeutic Approach to Duchenne Muscular Dystrophy

Johnny Huard,Chieh Tseng,Matthieu Huard,Mikhail G Kolonin,Yongmei Yu,Zhanguo Gao,Aiping Lu,Alexes C Daquinag,Xueqin Gao

doi:10.3390/biom11101519

Abstract

Duchenne muscular dystrophy (DMD), caused by the loss of dystrophin, remains incurable. Reduction in muscle regeneration with DMD is associated with the accumulation of fibroadipogenic progenitors (FAPs) differentiating into myofibroblasts and leading to a buildup of the collagenous tissue aggravating DMD pathogenesis. Mesenchymal stromal cells (MSCs) expressing platelet-derived growth factor receptors (PDGFRs) are activated in muscle during DMD progression and give rise to FAPs promoting DMD progression. Here, we hypothesized that muscle dysfunction in DMD could be delayed via genetic or pharmacologic depletion of MSC-derived FAPs. In this paper, we test this hypothesis in dystrophin-deficient mdx mice. To reduce fibro/adipose infiltration and potentiate muscle progenitor cells (MPCs), we used a model for inducible genetic ablation of proliferating MSCs via a suicide transgene, viral thymidine kinase (TK), expressed under the Pdgfrb promoter. We also tested if MSCs from fat tissue, the adipose stromal cells (ASCs), contribute to FAPs and could be targeted in DMD. Pharmacological ablation was performed with a hunter-killer peptide D-CAN targeting ASCs. MSC depletion with these approaches resulted in increased endurance, measured based on treadmill running, as well as grip strength, without significantly affecting fibrosis. Although more research is needed, our results suggest that depletion of pathogenic MSCs mitigates muscle damage and delays the loss of muscle function in mouse models of DMD.

Highlights

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophies caused by mutations in the dystrophin gene [1]
For genetic ablation of PDGFRβ+ lineage mesenchymal stromal cells (MSCs), we used Pdgfrb-thymidine kinase (TK) mice in which viral TK is expressed under the control of the PDGFRβ promoter [51]
The proliferation of plateletderived growth factor receptors (PDGFRs)+ fibroadipogenic progenitors (FAPs) is a requisite of both fibrosis and adipocyte expansion [52] demonstrated in DMD models [34] and models of aging [53]

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophies caused by mutations in the dystrophin gene [1]. In DMD patients, the loss of the sarcolemmal dystrophin complex reduces muscle membrane integrity and, triggers muscle fiber damage during muscle contraction [3,4,5,6,7,8]. This process results in an efflux of creatine kinase, an influx of calcium ions, and the recruitment of T cells, macrophages, and mast cells to the damaged muscle, contributing to progressive myofiber necrosis [8]. While several treatments have been approved for DMD, there is still no cure

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