CCR2 improves homing and engraftment of adipose-derived stem cells in dystrophic mice

Liang Wang,Jinfu Lin,Yu Zhang,Menglong Chen,Cheng Zhang,Ziyu Liao,Ruojie He,Huan Li

doi:10.1186/s13287-020-02065-z

Abstract

BackgroundDystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments. Systemic transplantation of adipose-derived stem cells (ADSCs) is a promising treatment approach, but its low efficacy remains a challenge. Chemokine system-mediated stem cell homing plays a critical role in systemic transplantation. Here, we investigated whether overexpression of a specific chemokine receptor could improve muscle homing and therapeutic effects of ADSC systemic transplantation in dystrophic mice.MethodsWe analysed multiple microarray datasets from the Gene Expression Omnibus to identify a candidate chemokine receptor and then evaluated the protein expression of target ligands in different tissues and organs of dystrophic mice. The candidate chemokine receptor was overexpressed using the lentiviral system in mouse ADSCs, which were used for systemic transplantation into the dystrophic mice, followed by evaluation of motor function, stem cell muscle homing, dystrophin expression, and muscle pathology.ResultsChemokine-profile analysis identified C–C chemokine receptor (CCR)2 as the potential target for improving ADSC homing. We found that the levels of its ligands C–C chemokine ligand (CCL)2 and CCL7 were higher in muscles than in other tissues and organs of dystrophic mice. Additionally, CCR2 overexpression improved ADSC migration ability and maintained their multilineage-differentiation potentials. Compared with control ADSCs, transplantation of those overexpressing CCR2 displayed better muscle homing and further improved motor function, dystrophin expression, and muscle pathology in dystrophic mice.ConclusionsThese results demonstrated that CCR2 improved ADSC muscle homing and therapeutic effects following systemic transplantation in dystrophic mice.

Highlights

Dystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments
CCR2 identification as a potential target for improving stem cell muscle homing in dystrophinopathy To determine a candidate chemokine axis, we evaluated four human microarray datasets (GSE465, GSE1004, GSE3307, and GSE6011) and six mouse microarray datasets (GSE1008, GSE1026, GSE1025, GSE897, GSE7187, and GSE1471)
Our results showed that dystrophin was expressed evenly in the sarcolemma of C57BL/6 J (C57) mice but at very low levels in the muscle of mdx + phosphate-buffered saline (PBS) mice (Fig. 7a–d), which was consistent with the percentage of revertant fibres in mdx mice (< 1%) [8, 39, 40]

Summary

Introduction

Dystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments. Systemic transplantation of adipose-derived stem cells (ADSCs) is a promising treatment approach, but its low efficacy remains a challenge. Chemokine system-mediated stem cell homing plays a critical role in systemic transplantation. We investigated whether overexpression of a specific chemokine receptor could improve muscle homing and therapeutic effects of ADSC systemic transplantation in dystrophic mice. Dystrophinopathy is a common X-linked recessive neuromuscular disorder characterised by progressive muscle wasting and weakness [1]. Its pathogenic gene is DMD; mutation in DMD causes absence of dystrophin, a protein located on the cytoplasmic surface of the sarcolemma [2]. Loss of dystrophin function results in sarcolemma instability, which causes pathological alterations in muscles, such as necrosis, repeated cycles of myofibre regeneration, and fibrosis [2]. Development of an effective treatment strategy for dystrophinopathy is critically important

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Results

Conclusion