Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing

Abstract

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Keywords: Diabetes; Exosomes; Immune regulation; MSCs; Regeneration; ncRNAs.

Fig. 1

Wound healing phases. Wound healing is a remarkably sophisticated biological process that can be categorized into four chronologically sequential and overlapping phases including hemostasis, inflammation, proliferation, and remodeling. Multiple cell-secreted factors and cells within the wound lesion, mainly including fibroblasts, keratinocytes, endothelial cells, and immune cells, are critical for remodeling wound healing. Platelets are pivotal in maintaining the hemostatic phase. Immune cells play an anti-infective role mainly during the inflammatory phase. Cell proliferation, migration, re-epithelialization, neovascularization, and extracellular matrix production are key biological events during these phases. During the remodeling phase, collagen I gradually replace collagen III in the wound site. It was created by taking the template on BioRender.com as a reference, with permission

Fig. 2

The biogenesis, identification, and components of exosomes. Various components of exosomes, including proteins, lipids, and molecule metabolites, are endocytosed to form early endosomes. Afterward, early endosomes are transformed into late endosomes, which subsequently form multivesicular bodies (MVBs). MVBs can fuse with the plasma membrane through a network of microtubules and cytoskeleton and release exosomes. Exosomes contain a variety of cellular components with a lipid bilayer structure and express a series of characteristic, conserved, key markers associated with exosome biosynthesis, including nucleic acids (DNAs, mRNAs, miRNAs, circRNAs, lncRNAs), biogenesis-related proteins (Alix, TSG101), membrane transport and fusion proteins (Annexin, Rab5), transmembrane proteins (CD9, CD63, CD81), antigen presentation (MHC-I and MHC-II), adhesion molecules, receptors (EGFR), enzymes (GAPDH, ATPase), lipids, metabolites. MVBs, multivesicular bodies; MHC, major tissue compatibility complexes

Fig. 3

Stem cell sources and other sources of exosomes for diabetic wound healing. Exosomes derived from MSCs have superior potential in the field of diabetic wound healing, including BMSCs ADSCs, PMSCs, HFMSCs, ESCs, MenSCs, hUSCs, iPSCs, and GMSCs. Besides, Other sources of exosomes are also potential candidates for wound healing, including blood, milk, cerebrospinal fluid, tears, tumor tissue, immune cells, keratinocytes, dermal fibroblasts, and HUVECs. It was created with BioRender.com

Fig. 4

The roles and mechanisms of exosome-carried ncRNAs and proteins in diabetic wound healing. Exosome-carried ncRNAs and proteins promote the activity and function of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds. Specifically, these loaded exosomes contribute to behavior alterations of skin cells, such as proliferation, migration, polarization, invasion, and viability, consequently leading to extracellular matrix remodeling, re-epithelialization, anti-inflammatory response, and angiogenesis. These effects act synergistically and ultimately accelerate diabetic wound healing. It was created with BioRender.com