TABLE 6.

MSC-sEVs exert curative effects by optimizing fibroblast behavior.

MSC source	Isolation	Target cells/conditions	Functional cargo	Molecules/Pathways affected	Key functions/Downstream genes	Ref
BM	Ultracentrifugation	cutaneous wound in rats; HaCaT, HDFs	—	TGF-β1↓→Smad2/3/4↓; TGF-β3↑, Smad7↑	Improved anti-fibrotic and scar-less wound healing	Jiang et al. (2020a)
Menstrual blood	Ultracentrifugation	cutaneous wound in diabetic mice	—	Col1/Col3↓	Reduced cellularity in granulation tissue and diminished scar formation	Dalirfardouei et al. (2019)
Modified synovium	Ultracentrifugation	cutaneous wound in diabetic rats; HDFs	MiR-126	p-AKT↑, p-ERK1/2↑	Accelerated re-epithelialization and collagen maturity in vivo; boosted migration and proliferation of HDFs	Tao et al. (2017)
AT	—	HDFs	miRs (-4484, -619-5p, -6879-5p)	Col Ⅰ↑, Elastin↑, KGF↑, CD34↑, VEGF↑	Boosted proliferation and migration of HDFs	Choi et al. (2018)
BM	Polymer precipitation and ultracentrifugation	HDFs	Wnt3a	—	promoted proliferation and migration abilities	McBride et al. (2017)
Fetal dermal	Polymer precipitation	skin wounds in mice; HDFs	Jagged 1	Notch 1↑ → Hes 1↑→ PCNA↑, CK19↑	Promoted proliferation, migration and secretion abilities in vitro and in vivo	Wang et al. (2019a)
BM	Ultracentrifugation	3D human Skin Organotypic model; HDFs, HaCaT	—	—	Faster re-epithelialization; enhanced proliferation and migratory capacity in vitro	Tutuianu et al. (2021)
Murine BM	ultracentrifugation	DFU model in mice; HDF	LncRNA H19	miR-152-3p↓ → PTEN↑ → p85PI3K↓→p-AKT↓	Improved proliferation and migration and suppressed apoptosis in vitro and in vivo	Li et al. (2020)
Thrombin pretreated hucb	Ultracentrifugation	cutaneous wound in rats; HDFs	angiogenin, angiopoietin-1, HGF, VEGF	p-ERK1/2↑, p-AKT↑	elevated proliferation and migration activity of HDFs; faster wound healing in vivo	Sung et al. (2019)
Huc	Ultracentrifugation	HDFs; skin wounds in mice	miR-21, -23a, -125b, -145	TGF-β2↓, Smad2↓	Suppression of myofibroblasts transformation or scar formation	Fang et al. (2016)
Huc	Ultracentrifugation	HaCATs, MDF; second-degree burn in rats	14-3-3ζ	YAP + p-LAS → p-YAP↑, cytoplasmic retention of YAP↑, a-SMA↓, col I↓ and col III↓	Reduced skin cell proliferation and nuclear translocation of β-catenin under high cell density in vitro; restricted excessive cell expansion and collagen deposition during remodeling period in vivo	Zhang et al. (2016)
AT	Polymer precipitation	skin wounds in mice; HDF		ERK/MAPK↑→MMP3/TIMP1↑, TGF-β3/TGF-β1↑, Col Ⅲ/Col Ⅰ↑	Mitigated myofibroblast differentiation; optimized ECM remodeling and lessened scar formation in vivo	Wang et al. (2017)
TSG-6 modified BM	Polymer precipitation	skin wounds in mice	TSG-6	TGF-β1↓, p-SMAD2Ser467/3S423/S425↓→ col I↓, col III↓, α-SMA↓; MCP-1↓, TNF-α↓, IL-1β↓, IL-6	prevented inflammation and collagen deposition, restricted scar formation in vivo	Jiang et al. (2020b)
Huc	ultracentrifugation	Skin wound in rats; HDF	miR-21-5p, -125b-5p	TGFBR1↓, TGFBR2↓, α-SMA↓, collagen I↓	Suppressed myofibroblast differentiation and scar formation, improved regenerative healing	Zhang et al. (2021)

BM, bone marrow; HaCaT, human immortal keratinocyte line; HDF, human dermal fibroblast; TGF-β, transgenic growth factor β; Huc, human umbilical cord; MDFs, mouse dermal fibroblasts; YAP, Yes-associated protein; LAS, large tumor suppressor; AT, adipose tissue; Erk, extracellular regulated kinase; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; MCP, monocyte chemoattractant protein-1; TNF-α, tumor necrosis factor-α; TGFBR, TGF-β, receptor type II.