Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis

Abstract

Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression.

Novel trends in application of stem cells in skin wound healing

“…It was also shown on diabetic mice model, that BM-MSCs enhance wound healing among others by decreasing MMPs expression, resulting in improved collagen 1 content (Xu et al, 2017).…”

<p>Anti-Inflammatory Effects of Magnetically Targeted Mesenchymal Stem Cells on Laser-Induced Skin Injuries in Rats</p>

“…With the development of regenerative technologies, stem cell therapy has emerged as a promising and attractive strategy to enhance tissue regeneration, cutaneous homeostasis, and wound healing. [1][2][3][4] Bone marrow-derived mesenchymal stem cells (BM-MSCs), also known as stromal progenitor cells, possess the ability to self-renew, expand rapidly, and differentiate into various tissue types via asymmetric replication. [5][6][7] Mesenchymal stem cells (MSCs) express low levels of major histocompatibility complex molecules, and this allows their allogeneic and xenogeneic applications.…”

Comprehensive Analysis of Differentially Expressed miRNAs and mRNAs Reveals That miR-181a-5p Plays a Key Role in Diabetic Dermal Fibroblasts

“…Deregulations of membrane transport, topological incorrect protein response, material metabolism, transcription, and translation are basic mechanisms that underlie these changes. Indeed, diabetic dermal fibroblasts had shown decreased collagen synthesis [ 22 ] and increased MMP production [ 23 ] compared with normal dermal fibroblasts. As the synthesis and secretion process of these proteins requires transcription, translation, membrane transport, and material metabolism, there is no doubt that they are dysregulated in diabetic HDFs.…”