Free-cell Therapeutics and Mechanism of Exosomes from Adipose-derived Stem Cells in Promoting Wound Healing: Current Understanding and Future Applications

0
0
0

Free-cell Therapeutics and Mechanism of Exosomes from Adipose-derived Stem Cells in Promoting Wound Healing: Current Understanding and Future Applications

Wound healing is a complex pathophysiological process involving tissue regeneration, repair, and reconstruction following injury. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option for wound repair due to their multidirectional differentiation potential, ability to promote cell proliferation and growth, and nerve regeneration functions. Exosomes derived from ADSCs (ADSC-Exos) have garnered significant attention for their tissue repair capabilities, as they are enriched with critical wound healing factors such as vascular endothelial growth factor A, fibroblast growth factor 2, hepatocyte growth factor, and platelet-derived growth factor subunit BB. This article provides a comprehensive overview of the mechanisms by which ADSC-Exos promote wound healing, their roles in different stages of the healing process, and their potential future applications.

The Role of ADSC-Exos in Wound Healing

Wound healing is a multi-stage process that includes inflammation, angiogenesis, proliferation, tissue remodeling, and scar repair. ADSC-Exos play a pivotal role in each of these stages by modulating cellular responses and signaling pathways.

Anti-inflammatory Effects in the Early Stage of Wound Healing

In the initial phase of wound healing, inflammatory responses such as hyperemia, white blood cell infiltration, and local redness and swelling are observed. ADSC-Exos exert anti-inflammatory effects primarily through their protein and RNA content. Macrophages are crucial during the inflammatory phase, and their accumulation in the wound site accelerates healing in both normal and diabetic mice. ADSC-Exos can be internalized by macrophages, where they activate the signal transducer and activator of transcription 3 (STAT3) pathway. This activation induces the polarization of macrophages to the M2 phenotype, which is associated with reduced inflammation. Additionally, ADSC-Exos overexpressing nuclear factor-E2-related factor 2 (Nrf2) have been shown to significantly decrease levels of inflammatory cytokines like interleukin-1b, interleukin-6, and tumor necrosis factor-alpha in diabetic rats.

Angiogenesis Promotion

Angiogenesis is a critical step in wound healing, involving the expression of various angiogenic factors. ADSC-Exos have been found to promote angiogenesis through multiple mechanisms. For instance, exosomal microRNA-181b-5p upregulates vascular endothelial growth factor (VEGF), enhancing the migration and formation rates of cerebral vascular endothelial cells under hypoxic conditions. Similarly, miR-21 overexpression in ADSC-Exos significantly promotes angiogenesis in human umbilical vein endothelial cells by activating the Akt and extracellular regulated protein kinases (ERK) pathways. ADSC-Exos also contain other vascular growth factors such as thrombopoietin, milk fat globule epidermal growth factor 8, and angiopoietin-like protein 1, which further support angiogenesis. Matrix metalloproteinases carried by exosomes also play a role in activating angiogenic factors.

Fibroblast Proliferation and Collagen Production

The proliferation and differentiation of fibroblasts mark the beginning of new tissue formation. ADSC-Exos have been shown to significantly enhance the proliferation and migration of fibroblasts in a dose-dependent manner. Treatment with ADSC-Exos increases the mRNA and protein levels of type I collagen, type III collagen, transforming growth factor beta 1, and basic fibroblast growth factor in fibroblasts. However, it is important to note that exogenous ADSC-Exos promote collagen expression primarily in the early stages of wound repair, while inhibiting collagen production in the later stages.

Signaling Pathways Involved in Wound Healing

ADSC-Exos promote wound healing through several key signaling pathways, including the transforming growth factor-beta (TGF-β), ERK/mitogen-activated protein kinases (ERK/MAPK), phosphatidylinositol 3-kinases/Akt (PI3K/Akt), Wnt/β-catenin, and Janus kinase-STAT (JAK-STAT) pathways. These pathways regulate cell proliferation, differentiation, inflammation, and apoptosis, and they are interconnected in their roles in wound healing.

  • TGF-β Signaling Pathway: The TGF-β family ligand dimer forms complexes with type II and type I receptors on the cell membrane. The type I receptor is phosphorylated by the type II receptor, activating downstream Smad proteins. Smad2/3 is phosphorylated and binds to Smad4, which then translocates into the nucleus to regulate target gene transcription.

  • ERK/MAPK Signaling Pathway: This pathway involves the sequential activation of rat sarcoma, rapidly accelerated fibrosarcoma, mitogen-activated protein kinase, and ERK. Activated ERK further activates downstream pathways, regulating cell proliferation, differentiation, and stress responses.

  • PI3K/Akt Signaling Pathway: PI3K, composed of regulatory subunit p85 and catalytic subunit p110, activates Akt when bound to growth factor receptors. Phosphorylated Akt activates downstream mammalian target of rapamycin (mTOR) targets, regulating cell proliferation, differentiation, apoptosis, and migration.

  • Wnt/β-catenin Signaling Pathway: When WNT binds to the membrane receptor Frizzled, the intracellular protein dishevelled is activated, stabilizing free β-catenin in the cytoplasm. β-catenin then enters the nucleus and binds to T-cell factor/lymphoid enhancing factor transcription factors, activating downstream target gene transcription.

  • JAK-STAT Signaling Pathway: Cytokines or growth factors bind to receptors, activating JAK, which phosphorylates tyrosine residues of downstream target proteins. Transcription factor STAT is recruited and phosphorylated, entering the nucleus as a dimer to regulate gene transcription.

Future Applications and Research Directions

The potential applications of ADSC-Exos in wound healing are vast, but further research is needed to optimize this cell-free therapeutic strategy. One promising direction is the combination of ADSC-Exos with other biological materials to enhance their therapeutic effects. Additionally, co-culturing ADSC-Exos with exosomes from other types of mesenchymal stem cells could yield synergistic effects.

Gene overexpression is another area of interest. For example, clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology could be used to overexpress or structurally modify genes that promote wound healing. These edited genes could then interact with exosomes to produce positive effects.

Conclusion

ADSC-Exos represent a novel and promising approach to wound healing, with the potential to modulate various stages of the healing process through multiple signaling pathways. While the research on ADSC-Exos is still in its early stages, the existing evidence suggests that they could revolutionize the treatment of wounds, particularly in challenging cases such as diabetic foot ulcers. Future studies should focus on optimizing the therapeutic use of ADSC-Exos, exploring their combination with other biological materials, and investigating the potential of gene editing technologies to enhance their efficacy.

doi.org/10.1097/CM9.0000000000001857

Was this helpful?

0 / 0