Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing

Abstract

Wound healing is a dynamic and highly sequential process involving a series of overlapping spatial and temporal phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal, multidirectional differentiation potential, and paracrine regulation. Exosomes are subcellular vesicular components 30-150 nm in size and are novel carriers of intercellular communication in regulating the biological behaviors of skin cells. Compared to MSCs, MSC-derived exosomes (MSC-exos) possess lower immunogenicity, easy storage, and highly effective biological activity. MSC-exos, mainly derived from adipose-derived stem cells (ADSCs), bone marrow-derived MSCs (BMSCs), human umbilical cord MSCs (hUC-MSCs), and other stem cell types, play a role in shaping the activity of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds, inflammatory wound repair, and even wound-related keloid formation. Therefore, this study focuses on the specific roles and mechanisms of different MSC-exos in wound healing, as well as the current limitations and various perspectives. Deciphering the biological properties of MSC-exos is crucial to providing a promising cell-free therapeutic tool for wound healing and cutaneous regeneration.

Keywords: Exosomes; Regeneration; Stem cells; Wound healing; lncRNA; miRNA.

Fig. 1

Wound types, skin structure, and wound healing phases. a Different wound types, mainly including infectious, diabetic, tumor, pressure, burn, and other wounds, such as trauma, radiation, drug-induced, ischemia and venous congestion wounds. b The skin structure consists of three layers, the epidermis, dermis, and hypodermis. The epidermis is primarily composed of keratinocytes, melanocytes, and Langerhans cells, contributing to a natural barrier against foreign objects. The dermis is a region rich in fibroblasts and immune cells, as well as collagen fibers, elastic fibers, reticular fibers, nerve endings, and capillaries, for maintaining the density and tightness of skin structure. The underlying hypodermis consists of adipocytes and connective tissue, which is conducive to warmth, cushioning, and reduction of mechanical stress. c The phase of wound healing is temporally overlapping and interdependent, including hemostasis, inflammation, proliferation, and tissue remodeling. Fibroblasts, keratinocytes, and immune cells are important skin cells in wound healing phases. In this figure was partly generated using Servier Medical Art (https://smart.servier.com), provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://creativecommons.org/licenses/by/3.0/)

Fig. 2

The compositions, biomarkers, and source of MSC-exos. Compared to normal exosomes, MSC-exos display similar compositions and biomarkers, which are related to biogenesis-related proteins (Alix, TSG101), membrane transport and fusion proteins (Annexin, Rab5), tetraspanins (CD81, CD63, CD9), specific receptor (EGFR), and antigen presentation (MHC, HLA-G). Various components, mainly metabolites, proteins, enzymes, HSPs, DNAs, mRNAs, miRNAs, lncRNAs, and circRNAs, are enclosed within MSC-exos. Multiple stem cell exosomes have good potential in wound healing, including ADSCs, BMSCs, hUC-MSCs, iPSCs, EPSCs, USCs, OMLP-PCs, MenSCs, WJ-MSCs, hAMSCs, hAFSCs, and hESCs. EGFR, epidermal growth factor receptor; MHC, major histocompatibility complex class; HLA-G, human leukocyte antigen-G; HSPs, heat shock proteins; mRNAs, messenger RNAs; miRNAs, microRNA; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs. In this figure was partly generated using Servier Medical Art (https://smart.servier.com), provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://creastivecommons.org/licenses/by/3.0/)

Fig. 3

The roles and mechanisms of various MSC-exos in promoting wound healing. MSC-exos, represented by ADSCs, BMSCs, hUC-MSCs, and other stem cell types, play a role in shaping the activity of fibroblasts, KCs, immune cells, and ECs. Specifically, the uploaded and shuttled proteins and ncRNAs within MSC-exos can trigger behavioral alterations in skin cells, such as proliferation, migration, invasion, differentiation, and polarization, consequently leading to angiogenesis, anti-inflammatory factor secretion, ECM reconstruction, anti-scarring effects, and tissue regeneration. Ultimately, these effects synergistically contribute to the accelerated or anti-scarring wound healing process. Figure 3 is partly generated using Servier Medical Art (https://smart.servier.com), provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://creastivecommons.org/licenses/by/3.0/)