MSC-derived sEV-loaded hyaluronan hydrogel promotes scarless skin healing by immunomodulation in a large skin wound model

Abstract

Designing hydrogel-based constructs capable of adjusting immune cell functions holds promise for skin tissue regeneration. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have attracted increasing attention owing to their anti-inflammatory and proangiogenic effects. Herein, we constructed a biofunctional hydrogel in which MSC-derived sEVs were incorporated into the injectable hyaluronic acid (HA) hydrogel, thus endowing the hydrogel with immunomodulatory effects. When implanted onto the wound site in a mouse large skin injury model, this functional hydrogel facilitates wound healing and inhibits scar tissue formation by driving macrophages towards an anti-inflammatory and anti-fibrotic (M2c) phenotype. Further investigation showed that the M2c-like phenotype induced by MSC-derived sEVs markedly inhibited the activation of fibroblasts, which could result in scarless skin wound healing. Taken together, these results suggest that modulation of the immune response is a promising and efficient approach to prevent fibrotic scar formation.

Adipose tissue-derived small extracellular vesicles modulate macrophages to improve the homing of adipocyte precursors and endothelial cells in adipose tissue regeneration

“…Previous studies demonstrated macrophages played diverse functions, including scavenging debris ( Peng et al, 2007 ; Wynn and Vannella, 2016 ), recruiting host cells ( Wang et al, 2018 ), promoting vascularization ( Sun et al, 2017 ), and inducing cell differentiation ( Wang et al, 2017 ). Most previous studies focused on the anti-inflammation ability of sEVs to polarize M1 macrophages to M2 macrophages ( Kwak et al, 2022 ; Li et al, 2022 ; Liu et al, 2022 ; Tang et al, 2022 ; Yang et al, 2022 ; Zhao et al, 2022 ). However, the role of macrophages in cell recruitment was largely unknown, especially in the process of tissue regeneration induced by sEVs.…”

Drug Release and Cytotoxicity of Hyaluronic Acid and Zinc Oxide Gels, An In-Vitro Study

“…It was concluded that HA-based hydrogels possessed great potential in chronic wound dressings [ 39 ]. Another study in a large skin wound model used a biofunctional hydrogel in which mesenchymal stem cell-derived small extracellular vesicles were incorporated into the injectable hyaluronic acid hydrogel and found that they induced immunomodulatory effects, thereby leading to a scarless wound healing [ 40 ].…”

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

“…This method can also involve adding polymers that can self-assemble directly to the EV suspension. For example, when two self-assembling polymers, HA-AD and HA-CD, were dissolved in a suspension of EVs, and they rapidly assembled to form a hydrogel encapsulating the EVs [ 170 ].…”