Table 7.

Role for EVs as a therapeutic.

Model	EV Source	Dose	EV Marker	Result	References [#]
Sprague-Dawley Partial Hepatectomy (PH)	Human liver stem cells	EVs (i.v.) 30 μg/mL immediately following PH	None reported	HLSC-EVs promote hepatocyte proliferation and reduce apoptosis. Effect is abrogated when HLSC-EVs are treated with RNAse   HLSC-EVs promote functional and morphological recovery of the liver through an RNA-dependent mechanism	[194]
C57BL/6J PH I/R	Mouse hepatocytes, Kupffer cells, liver sinusoidal endothelial cells	EVsa (i.v.) after surgery and again at 24 h EVs 24 and 48 h after I/R	TSG101/CD81/CD63 Positive EAA-1 and GRP78 Negative	Hepatocyte derived—EVs, but not other liver EVs, induce hepatocyte proliferation in vitro and in vivob   Hepatocyte-EVs deliver SK2 to target cells allowing local production of S1P, stimulating proliferation and reducing apoptosis	[137]
C57BL/6c	Human umbilical cord	CCl4 0.05 mL/kg (i.p.) followed by 0.4 μg MSC-EVs by intrasplenic injection	None reported	Increased PCNA and Cyclin D1, suggests increased proliferation	[188]
Wistar RatHepG2	Bone marrow derived from Wistar Rats	CCl4 20% (v/v), 5 mL/kg (i.p.). 24 h later HPV 50 μg MSC-EVs   In vitro: APAP 8 mmol/L cotreatment with 0.5 μg/mL MSC-EVs	CD9/CD63/CD81	In vivo: demonstrates MSC-EVs have greater potency than MSCs to mitigate liver injury   >In vitro: Increased cell viability, and decreased ROS in MSC-EVs + APAP compared to APAP alone	[189]
Balb/c—nu/nu Female	Human umbilical cord	0.15–0.35 mL/kg CCl4 at 10% conc. in mineral oil (i.p.) 24 h later 8, 16, or 32 mg/kg via tail vein or oral gavage	CD9/CD63	Dose-dependent protective effect for MSC-EVs, oral gavage compared to tail vein injection of MSC-EVs results in similar efficacy profiles   MSC-EVs deliver GPX1 to target hepatocytes and reduce oxidative stress and apoptosis	[191]
CD-1 micec	Femur bone marrow of CD-1	350 mg/kg APAP (i.p.) followed by 5 mg of MSC + soluble factors	–	Compares ncMSCs to hcMSCS, hcMSCs more effective at reducing liver damage, hcMSCs enriched in proteins involved in intracellular transport and cellular respiration	[192]
BalB miced Femur bone marrow of CD-1	Femur bone marrow of CD-1	270 mg/kg APAP (i.p.) 4 h later injected with 1 mL ncMSC or hcMSC (0.5 mL conditioned media to 0.5 mL lysate, protein conc. 10 mg/mL)	–	10–30 kDa fraction from hypoxic cells reduce liver injury, fraction enriched in 10 proteins	[199]

Unless otherwise reported, EVs were collected via ultracentrifugation at 100,000 g.

^aEV dose not reported.

^bNot directly reported, references two papers that characterize multiple methods.

^cTFF, Tangential flow filtration, followed by HPLC, further concentrated by using 100 kDa MWCO filter.

^dCells cultured in hypoxic conditions (5% O₂) = hcMSCs, cells cultured in normal oxygen conditions (21% O₂) = ncMSCs.