Differential Wound Healing Capacity of Mesenchymal Stem Cell-Derived Exosomes Originated From Bone Marrow, Adipose Tissue and Umbilical Cord Under Serum- and Xeno-Free Condition.

Diem Huong Hoang,Nhung Thi My Hoang,Hoang-Phuong Nguyen,Phuong Thi Minh Dam,Tu Dac Nguyen,Xuan-Hung Nguyen,Phuong Thi Xuan Do,Uyen Thi Trang Than,Hue Thi Hong Bui,Mai Quynh Trinh,Van Duc Dang,Liem Nguyen Thanh,Duc Minh Vu

doi:10.3389/fmolb.2020.00119

Diem Huong Hoang, Nhung Thi My Hoang + Show 11 more

Open Access

https://doi.org/10.3389/fmolb.2020.00119

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Abstract

Exosomes are nano-scale and closed membrane vesicles which are promising for therapeutic applications due to exosome-enclosed therapeutic molecules such as DNA, small RNAs, proteins and lipids. Recently, it has been demonstrated that mesenchymal stem cell (MSC)-derived exosomes have capacity to regulate many biological events associated with wound healing process, such as cell proliferation, cell migration and blood vessel formation. This study investigated the regenerative potentials for cutaneous tissue, in regard to growth factors associated with wound healing and skin cell proliferation and migration, by exosomes released from primary MSCs originated from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) under serum- and xeno-free condition. We found crucial wound healing-mediated growth factors, such as vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), and platelet-derived growth factor BB (PDGF-BB) in exosomes derived from all three MSC sources. However, expression levels of these growth factors in exosomes were influenced by MSC origins, especially transforming growth factor beta (TGF-β) was only detected in UCMSC-derived exosomes. All exosomes released by three MSCs sources induced keratinocyte and fibroblast proliferation and migration; and, the induction of cell migration is a dependent manner with the higher dose of exosomes was used (20 μg), the faster migration rate was observed. Additionally, the influences of exosomes on cell proliferation and migration was associated with exosome origins and also target cells of exosomes that the greatest induction of primary dermal fibroblasts belongs to BMMSC-derived exosomes and keratinocytes belongs to UCMSC-derived exosomes. Data from this study indicated that BMMSCs and UCMSCs under clinical condition secreted exosomes are promising to develop into therapeutic products for wound healing treatment.

Highlights

Wound healing is a complex process to restore the structure and function of damaged tissues
Data showed that only UCMSCs expressed their cellular senescence with 0.18%, but there was no senescence signs observed in ADMSCs and BMMSCs (Table 1; Figure 2)
In order to compare the secretome characteristic of human primary mesenchymal stem cells (MSCs)-derived exosomes originated from adipose tissue (AD), bone marrow (BM), and umbilical cord (UC) tissues, we evaluated a panel of growth factors including vascular endothelial growth factor (VEGF)-A, fibroblast growth factor (FGF)-2, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF)-BB, and transforming growth factor (TGF)-β1 using Luminex assay (Table 2)

Summary

Introduction

Wound healing is a complex process to restore the structure and function of damaged tissues. The healing process is divided into four overlapping phases of haemostasis, inflammation, proliferation, and remodeling, that are strictly regulated by multiple diverse growth factors, cytokines, enzymes and structural matrix proteins generated by multiple cell types such as dermal fibroblasts, epidermal keratinocytes, and immune cells (Sonnemann and Bement, 2011). Many treatment methods have been proposed for wound healing including cell therapy (Kanji and Das, 2017; Kosaric et al, 2019). Several factors secreted by MSCs with strong wound-healing potentials have been reported, including epidermal growth factor (EGF); interleukin-like growth factor (IGF); fibroblast growth factor (FGF); platelet-derived growth factor (PDGF); transforming growth factor (TGF); vascular endothelial growth factor (VEGF); interleukins (IL); interferon (IFN); stromal cell-derived factor-1 (SDF-1); and, tumor necrosis factor α (TNFα) (Hu et al, 2018). It is evidenced that the MSC secreted factors enveloped in enclosed vesicles named extracellular membrane vesicles (EVs) (Phinney and Pittenger, 2017)

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