Table 1.
Evidence and clues of EVs in promoting scarless wound healing, anti-aging and skin regeneration, and anti-pigmentation.
| Effect | Source of EVs | Model Used | Treatment Dose | Administration Method | Evidence and Clues | Reference |
|---|---|---|---|---|---|---|
| Scarless wound healing | ADSC-Exo | In vivo: Full-thickness dorsal wound in BALB/c mice model | 1000 µg/mL | IV | ↑ ratio of Col III:Col I, TGF-β3:TGF-β1, MMP-1 & MMP-3:TIMP-1 More flattened epidermal surface Well distributed collagen in the dermis with less cross-linking |
[36] |
| In vitro: Fibroblasts | 0, 25, 50 & 100 µg/mL | - | ↓ myofibroblast differentiation ↓ α-SMA & Col1A1 ↑ TGF-β3, Col3A1, MMP-1 & MMP-3 |
|||
| ADSC-Exo | In vivo: Excisional wound model in BALB/c mice | 700 μg/mL | SC | ↓ wound area ↓ Col I, Col III & α-SMA |
[33] | |
| In vitro: HSF | 20 μg/mL | - | ↓ proliferation & migration ↓ Col I, Col III & α-SMA |
|||
| ADSC-Exo | In vivo: Hypertrophic scar model in New Zealand rabbits | 0.1 mL | Local injection | ↓ α-SMA & Col I ↓ myofibroblast aggregation |
[44] | |
| ADSC-Exo | In vivo: Full-thickness wound in BALB/C mice | 1000 µg/mL | SC | ↑ angiogenesis ↑ re-epithelialization rate ↓ scar area ↑ dermis thickness & collagen deposition |
[45] | |
| In vitro: HDF | 0, 25, 50 & 100 μg/mL (Gene and protein expression analysis & Quantification of growth factor) 0, 50, and 100 μg/mL (proliferation & migration assay) |
- | ↑ Col I, Col III, MMP-1, bFGF & TGF-β1 level ↓ α-SMA ↑ proliferation & migration |
|||
| ADSC-MV | In vivo: Full-thickness wound in BALB/C mice | 50 μL | SC | ↑ re-epithelialization ↑ collagen deposition ↑ neovascularization ↓ wound edge (scar) |
[46] | |
| In vitro: HUVEC, HaCaT, HDF | 0, 5 & 10 μg/mL (migration assay) 0 & 20 μg/mL (proliferation, angiogenesis assay, gene and protein expression analysis) |
- | ↑ proliferation, migration & angiogenesis ↑ fibronectin in HUVEC, HaCaT & HDF ↑ Col I, Col III & elastin in HDF |
|||
| UCB-MSC-Exo | In vivo: Full-thickness excisional wound in SD rats | 200 μg/mL | Tail vein injection | ↑ wound closure ↓ scar formation ↑ skin appendages regeneration ↑ angiogenesis Regulated collagen fibers distribution |
[47] | |
| In vitro: HDF | 25 ng/mL | - | ↓ α-SMA & Col I ↑ proliferation & migration |
|||
| UCB-Exo | In vivo: Full-thickness wound in C57BL/6 mice | 2000 μg/mL | Local injection | ↑ re-epithelialization ↑ angiogenesis ↓ scar width |
[48] | |
| UC-MSC-Exo | In vitro: Fibroblasts | 50, 75 & 150 μg/mL | - | ↓ Col I, Col III & α-SMA | [49] | |
| UC-MSC-Exo | In vivo: Full-thickness excisional wound in BALB/C mice | 1000 μg/mL | SC | ↑ epidermal re-epithelialization & dermal angiogenesis ↓ α-SMA |
[50] | |
| In vitro: HaCaT | 125, 250, 500, 1000 ng/mL | - | ↑ proliferation & migration ↓ apoptosis |
|||
| hAEC-Exo | In vivo: Full-thickness excisional wound in SD rats | 25, 50 & 100 μg/mL | SC | Well-organized collagen fibers ↑ re-epithelialization |
[51] | |
| In vitro: HDF | 25, 50 & 100 μg/mL | - | ↓ Col I & Col III ↑ MMP-1 & TIMP-1 ↑ proliferation & migration |
|||
| hAFSC-Exo | In vivo: Full- thickness excisional wound in SD rats | 200 µg/mL | SC | Smoother wound edge ↑ hair follicle regeneration ↓ collagen fiber deposition ↑ nerve & vessel reconstruction ↑ cutaneous cell proliferation ↓ α-SMA, Col1A2, TGF-β1 & TIMP-1 ↑ Col3A1, TGF-β3, MMP-1 & MMP-3 |
[52] | |
| In vitro: HDF | 10 & 25 ng/mL | - | ↓ α-SMA | |||
| TSG-6 modified MSC-Exo | In vivo: Full-thickness wound model in C57BL/6J mice | 1000 µg/mL | SC | ↓ MCP-1, TNF-α, IL-1β, IL-6, TGF-β1, Col I, Col III & α-SMA | [32] | |
| iPSC-MSC-Exo | In vitro: HaCaT, HDF | 10 & 20 µg/mL | - | ↑ proliferation & migration ↑ Col1A1, elastin & MMP-1 in HDF ↑ Col1A1 & elastin in HaCaT |
[53] | |
| BM-MSC-Exo | In vitro: HaCaT, HDF, EAhy926 line, Human monocytic cell U937 | N/S | - | Not changes in TNF-α release by activated macrophages ↑ angiogenesis ↑ proliferation & migration of skin cells ↓ Col I, Col III, α-SMA, MMP-2 & MMP-14 as well as ↑ MMP-13 expression in myofibroblasts at the gene level ↑ Col I expression of myofibroblasts at the protein level ↑ decorin & fibronectin expression of fibroblasts at the protein level |
[54] | |
| BM-MSC-Exo | In vivo: Full-thickness excisional wound in SD rat | 250 μg | IV | ↑ wound closure Restore skin function ↑ angiogenesis ↓ TGF-β1 |
[20] | |
| In vitro: HaCaT, HDF | 25 μg/mL | - | ↑ proliferation | |||
| Anti-aging and promoting skin regeneration. | ADSC-Exo | In vivo: Photoaging SD rats | 100 μL | SC | ↓ epidermal thickness ↑ dermal thickness |
[55] |
| In vitro: HDF | 12.5, 25, 50, 100 & 200 μg/mL | - | ↑ Col I ↓ Col III, MMP-1 & MMP-3 |
|||
| ADSC-EV | In vivo: Photoaging BALB/c nude mice | 150 & 300 μg/mL | SC | ↓ skin wrinkle ↑ epidermal cell proliferation ↓ macrophage infiltration & ROS production |
[15] | |
| In vitro: Photoaging HDF, 264.7 cells | 50, 100, 150 & 200 μg/mL (HDF activity) 100 & 200 μg/mL (Macrophage differentiation, gene expression analysis & protein expression analysis) |
- | ↑ HDF activity & protected HDFs from UVB-induced senescence ↓ Col I ↑ MMP-3 ↓ M0 to M1 differentiation of macrophages ↑ SOD-1 & CAT Rescue HDFs from cell cycle arrest |
|||
| ADSC-Exo | In vitro: UVB- irradiated HDF | N/S | - | ↑ cell migration & proliferation ↓ MMP-1, -2, -3 & -9 ↑ Col I, II, III, V & elastin ↑ TIMP-1 & TGF-β1 |
[56] | |
| ADSC-Exo | In vitro: HDF | N/S | - | ↓ UVB-induced DNA damage, ROS production & MMP-1 ↑ procollagen type I |
[57] | |
| UC-MSC-EV & Fb-EV | In vitro: HDF | 0, 0.5 & 5 μg/mL | - | ↓ ROS production ↑ proliferation ↑ GPX-1 & Col I ↓ MMP-1 Protect cells against UVB- induced cell death & cell cycle arrest Protect cells against UVB-induced photoaging through antioxidant activity |
[58] | |
| iPSCs-Exo | In vitro: Photoaging and naturally senescent HDF | 20 × 108 particles/mL | - | ↓ cell damage ↓ SA-β-Gal & MMP-1/3 ↑ Col I |
[59] | |
| TB-Exo | In vitro: Intrinsically/extrinsically senescent HNDF | 1 × 104 & 1 × 105 particles/mL | - | ↑ cell migration & proliferation ↑ Col I, Col III, elastin & fibronectin |
[60] | |
| UC-MSC-Exo | Ex vivo: Photodamage skin model in SD rat | 200, 400 & 600 µg | - | ↓ skin photodamage | [61] | |
| In vitro: HaCaT | 600 µg | - | Protect cells from oxidative stress ↓ ROS production ↑ SIRT1 expression under oxidative stress condition Activate autophagy by delivery of 14-3-3ζ protein |
|||
| Anti-pigmentation | Mouse keratinocyte-Exo | In vitro: Mouse melanocytes | N/S | - | ↓ TYR, TYRP1, TYRP2 & MITF ↓ melanin content |
[62] |
| hAMSC- Exo | In vitro: B16F10 cells | N/S | - | ↓ TYR, TYRP1, TYRP2 & MITF ↓ melanin content ↑ LC3II ↓ p62 |
[63] | |
| UVA-exposed melanocyte-EV | In vitro: Keratinocytes, melanoma cells | N/S | - | ↑ BCL-xL & BCL-2 in keratinocytes ↓ PDCD4 & PTEN in keratinocytes ↑ proliferation & migration of keratinocytes and melanocytes |
[64] |
Abbreviations: Mesenchymal stem cell, MSC; Human amnion epithelial cell-derived exosome, hAEC-Exo; human amniotic fluid stem cells-derived exosome, hAFSC-Exo; Adipose-derived stem cell-extracellular vesicle, ADSC-EV; Adipose-derived stem cell exosome, ADSC-Exo; Adipose-derived MSC multivesicle, ADSC-MV; Bone marrow-derived MSC exosome, BM-MSC-Exo; Umbilical cord-derived MSC exosome, UC-MSC-Exo; Umbilical cord blood-derived MSC exosome, UCB-MSC-Exo; Umbilical cord blood-derived exosome, UCB-Exo; Induced pluripotent stem cell-derived MSCs-exosome, iPSC-MSC-Exo; Induced pluripotent stem cell-derived exosome, iPSC-MSC-Exo; Trophoblasts-derived exosome, TB-Exo; Fibroblast-extracellular vesicle, Fb-EV; Human amniotic mesenchymal stem cells derived exosome, hAMSC-Exo; Mouse keratinocyte derived exosome, Mouse keratinocyte-Exo; Ultraviolet A-exposed melanocyte-derived extracellular vesicle, UVA-exposed melanocyte-EV; Tumor necrosis factor stimulated gene-6 modified MSC-Exo, TSG-6 modified MSC-Exo; Sprague-Dawley, SD; Human umbilical vein endothelial cells, HUVEC; Human dermal fibroblasts, HDF; Hypertrophic scar tissue-derived fibroblasts, HSFs; Human normal dermal fibroblast, HNDF; Murine melanoma cell line from a C57BL/6J mouse, B16F10 cell; Immortalized human keratinocytes, HaCaT; Immortalized Human Vascular Endothelial Cells, EAhy926 line; monocyte-like cells, 264.7 cells; Ultraviolet, UV; ultraviolet B-rays, UVB; Intravenous, IV; Subcutaneous injection, SC; Not stated, N/S; Collagen, Col; Col1A1, Collagen type I alpha 1 chain; Col1A2, Collagen type I alpha 2 chain; Col3A1, Collagen type III alpha 1 chain; Matrix metalloproteinase, MMP; Tissue inhibitors of matrix metalloproteinase, TIMP; Transforming growth factor beta, TGF-β; Alpha-smooth muscle actin, α-SMA; basic fibroblast growth factor, bFGF; Tumor necrosis factor-alpha, TNF-α; Monocyte chemoattractant protein-1, MCP-1; Interleukin, IL; Reactive oxygen species, ROS; Superoxide dismutase type 1, SOD-1; Catalase, CAT; Glutathione peroxidase 1, GPX-1; Senescence-associated-β-galactosidase, SA-β-Gal; Sirtuin 1, SIRT1; Zeta, ζ; Microphthalmia-associated transcription factor, MITF; Tyrosinase, TYR; Tyrosinase-related protein, TYRP; Microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate, LC3-II; Tumor protein 62, p62; B-cell lymphoma-extra-large, BCL-xL; B-cell lymphoma 2, BCL-2, Phosphatase and tensin homolog, PTEN; Programmed cell death protein 4, PDCD4.