The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model

Haoyan Huang,Xiaohong Shen,Yuqiao Chang,Zhong-Chao Han,Shang Chen,Jun Zhang,Ying Chang,Zongjin Li,Hui Cheng,Nadia Benkirane-Jessel,Guoqiang Hua,Zhibo Han,Jiasong Cao,Zhikun Guo,Wei Du

doi:10.1186/s12951-022-01301-3

Abstract

BackgroundThe promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2.ResultsIn this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis.ConclusionsOur findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration.Graphical

Highlights

With an increase in the elderly population, the prevalence and incidence of peripheral artery disease (PAD) are increasing markedly and globally [1]
Prostaglandin E2 (PGE2)‐releasing profile To test whether the PGE2 matrix could release P GE2 for a prolonged time, we examined the release kinetics of the PGE2 matrix and free P GE2 in collagen in vitro and in vivo using ELISA
We found that free PGE2 in collagen (PGE2 group) showed an apparent burst release at the first two to three days

Summary

Introduction

With an increase in the elderly population, the prevalence and incidence of peripheral artery disease (PAD) are increasing markedly and globally [1]. When skeletal muscle is damaged by stimuli such as ischemia, resident muscle stem cells, termed satellite cells (SCs), become activated and immediately participate in regenerative processes through cell proliferation and differentiation to form new muscle fibers [6, 9]. Myogenic regulatory factors such as MyoD1 (myoblast determination protein 1) and Myf (myogenic factor 5) are specific markers that promote SC differentiation into myotubes and play a major role in the regulation of skeletal muscle regeneration during myogenesis [10, 11]. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2

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Results

Conclusion