Therapeutic potential of stem cell-derived exosomes in hair regeneration: A systematic review

Table 1 Summary of the main findings of included in vitro studies involving exosomes for hair regeneration

Ref.	Title	Country	Source of exosomes	Groups included in study	Results/key outcomes
Kazi et al[72], 2022	Dermal papilla cell-derived extracellular vesicles increase hair inductive gene expression in adipose stem cells via β-catenin activation	Japan	Dermal papilla cell-derived extracellular vesicles	Control group: ASCs without treatment; CAO1/2FP group: ASCs treated only with CAO1/2FP; DPC-EVs group: ASCs treated with 5 μg/mL of DPC-EVs and CAO1/2FP; P4 DPC-EVs group: ASCs treated with 5 μg/mL of early-passage (P4) DPC-EVs and CAO1/2FP; P5 DPC-EVs group: ASCs treated with 5 μg/mL of late-passage (P5) DPC-EVs and CAO1/2FP	Cell proliferation: P4 DPC-EVs significantly increased ASC proliferation compared to P5 DPC-EVs (P < 0.01); optimal concentration of 5 μg/mL DPC-EVs enhanced proliferation without toxicity
					Gene & protein expression: P4 DPC-EVs upregulated VCAN, α-SMA, OPN, and NCAM genes in ASCs (P < 0.05); western blot confirmed increased β-catenin and VCAN expression in treated ASCs
					MiRNA regulation: P4 DPC-EVs contained higher levels of mir-195-5P and mir-218-5P, both of which regulate hair follicle induction; mir-214-5P (a type of inhibitor of keratinocyte proliferation) was lower in P4 DPC-EVs compared to P5
					Exosome uptake & characterization: TEM analysis showed that DPC-EVs were 80-170 nm in diameter; CD63 and TSG101 confirmed as exosome markers via western blot; fluorescence microscopy demonstrated efficient DPC-EV uptake by ASCs
Nilforoushzadeh et al[73], 2020	Human hair outer root sheath cells and platelet-lysis exosomes promote hair inductivity of dermal papilla cell	Iran	HHORSCs and PL exosomes	Control group: hDPCs cultured without exosomes; HHORSC-Exo group: hDPCs treated with 25, 50, 100 μg/mL HHORSC-derived exosomes; PL-Exo group: hDPCs treated with 25, 50, 100 μg/mL PL-derived exosomes	Cell proliferation: HHORSC-Exo significantly increased hDPC proliferation compared to control and PL-Exo groups; MTS assay confirmed higher metabolic activity in HHORSC-Exo-treated
					Migration & inductive capacity: Transwell migration assay showed increased hDPC migration in HHORSC-Exo-treated cells compared to controls; PL-Exo had a less significant effect in both migration and proliferation analyses compared to HHORSC-Exo
					Gene & protein expression: HHORSC-Exo treatment upregulated ALP (by 2.1-fold), VCAN (by 1.7-fold), and α-SMA (by 1.3-fold) compared to control; flow cytometry confirmed high expression of VCAN (77%) and α-SMA (55.2%) in hDPCs
					Exosome characterization & internalization: Nanoparticle tracking analysis showed HHORSC- and PL-derived exosomes were 30-150 nm in size; western blot confirmed the presence of CD9, CD63, and CD81 in both HHORSC- and PL-Exos; fluorescence microscopy demonstrated efficient uptake of exosomes by hDPCs, with PL-Exo showing higher internalization efficiency (59.93%) than HHORSC-Exo (47.73%), but had weaker biological effects
Shieh et al[74], 2022	Bio-pulsed stimulation effectively improves the production of avian mesenchymal stem cell-derived extracellular vesicles that enhance the bioactivity of skin fibroblasts and hair follicle cells	Taiwan	Bio-pulsed AMSC-sEVs and control AMSC-sEVs were isolated from the bio-pulsed AMSC CM and control AMSC CM	Control group: HSFs without treatment; HFDPCs treated with control AMSC-sEV; HFDPCs treated with AMSC-sEVs, treatment with the bio-pulsed AMSC-sEVs	Furthermore, the bio-pulsed AMSC-sEVs, especially at the concentration of 70 μg/mL, enhanced wound healing in the HSFs within 24 hours

HHORSCs: Human hair outer root sheath cells; PL: Platelet lysis; AMSC: Avian-derived mesenchymal stem cell; sEVs: Small extracellular vesicles; CM: Conditioned medium; ASCs: Adipose-derived stem cells; DPC: Dermal papilla cell; EVs: Extracellular vesicles; hDPCs: Human dermal papilla cells; HSFs: Heat shock transcription factors; HFDPCs: Hair follicle dermal papilla cells; VCAN: Versican; α-SMA: Alpha-smooth muscle actin; OPN: Osteopontin; NCAM: Neural cell adhesion molecule; miRNA: MicroRNA; TEM: Transmission electron microscopy; TSG101: Tumor susceptibility gene 101; MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; ALP: Alkaline phosphatase.