Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease

Table 1 Mesenchymal stem cells treatments for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in vitro

Cell sources	Passage number	Cell models	Biological effects
Rat BM MSCs	P3-4	HepG2 cells	rMSCs alleviated cellular lipotoxicity and metabolic disturbance, primarily by regulating ER stress and calcium homeostasis via SERCA[34]
Mouse BM MSCs	P5-10	HepG2 cells	mBMSCs restored disordered glucose and lipid metabolism, as well as mitochondrial dysfunction in T2DM/NAFLD[35]
Human UC MSCs derived miR-24-3p	Not reported	Primary hepatocytes	hUC-MSC derived miR-24-3p suppressed lipid accumulation, ROS generation, and inflammatory response through targeting KEAP-1 signaling[37]
Human UC MSCs derived miR-627-5p	P3	L-02 cells	hUC-MSC-derived miR-627-5p improved glucose and lipid metabolism by targeting FTO[39]
Mouse AD MSCs derived miR-223-3p	P2 or above	NCTC1469 cells	mADSC-EV-derived miR-223-3p exhibited suppressive effects on lipid accumulation and liver fibrosis by inhibiting the target gene E2F1[42]
Human MenSCs	P2-3	L-02/AML12 cells	Hepatocyte growth factor secreted by MenSCs in NAFLD promoted hepatic glycogen storage and attenuated lipid accumulation through the downregulation Rnf186[43]
Human UC MSCs derived Exos	Not reported	HepG2/AML12 cells	hUC-MSC-Exos attenuated steatosis in hepatocytes and inhibited oxidative stress in NASH[45]
Mouse AD MSCs	P5-6	Murine hepatocyte cell line H2.35	mADSCs treatment alleviated lipotoxicity-induced apoptosis in steatotic hepatocytes by activating the Notch signaling pathway[46]
Human UC MSCs derived CM	Not reported	L-02 cells	hMSC-CM enhanced liver mitochondrial function while reducing inflammation and apoptosis by upregulating SIRT1[50]
Human UC MSCs derived Exos	P4-7	HepRG cells	hUC-MSC-Exos reduced inflammatory cytokines by inducing macrophage anti-inflammatory phenotypes[59]
Human CB MSCs derived Exos with curcumin	Not reported	HepG2 cells	MSC-Exos with curcumin improved cell viability and inhibited lipogenesis, while the anti-apoptotic pathway involved the downregulation of ASK1, JNK, and BAX genes[63]
Human UC MSC derived Exos	P3-4	L-02/AML12 cells	MSC-Exos inhibit lipid accumulation by promoting the β-oxidation of fatty acids and suppressing fatty acid synthesis[64]

MSCs: Mesenchymal stem cells; BM: Bone marrow; UC: Umbilical cord; AD: Adipose- derived; CB: Cord blood; Exos: Exosomes; EVs: Extracellular vesicles; T2DM: Type 2 diabetes mellitus; MenSCs: Menstrual blood-derived stem cells; mADSCs: Mouse adipose-derived stem cells; NAFLD: Non-alcoholic fatty liver disease.

Table 2 Mesenchymal stem cells treatments for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in vivo

MSC source	Passage number	Animal models	Other instructions	Biological effect
Mouse CB MSCs	P5-8	Mouse	1 × 106 cells/mouse injected (i.v.) at weeks 21 and 23	mMSCs transplantation decreased high-fat-induced weight gain, expansion of subcutaneous adipose tissue, steatosis, lobular inflammation, and liver fibrogenesis[33]
Rat BM MSCs	P3-4	Rat	2 × 106 cells/rat injected (i.v.) at weeks 18 and 20	rMSCs administration improved lipid metabolism and insulin sensitivity, and inhibited ER stress in the liver[34]
Mouse BM MSCs	P5-10	Mouse	1 × 107 cells/kg body weight injected (i.v.)	mBMSCs restored disordered glucose levels, reduced fat accumulation, and corrected mitochondrial dysfunction in mice with diabetes-associated NAFLD[35]
Human UC MSCs	P5	Rat	1 × 106 cells/rat injected (i.v.) at weeks 1 and 5	hUC-MSCs in combination with liraglutide improved glycolipid metabolism, insulin resistance, and liver injury in T2DM/NAFLD rats by downregulating TLR4/NF-κB inflammatory pathway and ameliorating oxidative stress[36]
Human UC MSCs derived miR-24-3p	Not reported	Mouse	120 μg/mouse injected (i.v.) weekly for 16 weeks	hUC-MSC-derived miR-24-3p alleviated lipid accumulation, inflammation, and oxidative stress in NAFLD[37]
Human UC MSCs	P3	Mouse	1 × 106 cells/mouse injected (i.v.) once a week for 6 weeks	hUC-MSCs improved glucose homeostasis and lipid metabolism, and alleviated hepatic steatosis and liver damage in obese T2DM/NAFLD mice[38]
Human UC MSCs derived miR-627-5p	P3	Rat	100 μg/rat injected (i.v.) once a week for 2 months	hUC-MSC-derived miR-627-5p improved glucose and lipid metabolism, and alleviated liver damage in NAFLD[39]
Rat AD MSCs	P3-15	Rat	2 × 106 cells/rat injected (p.v.)	rADSCs improved liver function and lipid metabolism, thereby exerting hepatoprotective effects[40]
Rat AD MSCs	P3	Rat	2 × 106 cells/rat injected (p.v.)	rADSCs improved liver function; reduced lipid accumulation, oxidative stress, and inflammation; and decelerated the progression of NAFLD in the rat model[41]
Mouse AD MSCs derived miR-223-3p	P2 or above	Mouse	100 μg/mouse injected (i.v.) twice a week for last 6 weeks	mADSC-EV-derived miR-223-3p attenuated lipid accumulation and fibrosis by negatively regulating E2F1 expression[42]
Human MenSCs	P2-3	Mouse	5 × 105 cells/mouse injected (i.v.) at weeks 16, 19, and 22	Hepatocyte growth factor secreted by MenSCs in fatty liver diseases promoted hepatic glycogen storage and attenuated lipid accumulation in NAFLD[43]
Human BM MSCs	P6-15	Mouse	(0.9-1) × 106 cells/mouse via splenic injection	hBMSCs reduced hepatic lipid content, inflammation, and fibrosis, as well as restored metabolic and tissue homeostasis, by donating human mitochondria to mouse hepatocytes[44]
Human UC MSCs derived Exos	Not reported	Mouse	100 μg/mouse injected (i.v.) twice a week for final 2 weeks	hUC-MSC-Exos attenuated steatosis, inflammatory responses, and oxidative stress in hepatocytes via the Nrf2/NQO-1 pathway[45]
Mouse AD MSCs	P5-6	Mouse	1 × 105 cells/mouse via splenic injection twice every 2 weeks for 12 weeks	mADSCs reduced apoptosis of steatotic hepatocytes and restored cellular proliferation by activating Notch signaling[46]
Rat BM MSCs/ Rat BM MSCs derived Exos	P4	Rat	1 × 106 cells/mouse injected (i.v.)/15/30/120 μg/kg body weight injected (i.v.) twice per week for 6 weeks	rBMSCs and rBMSC-Exos reduced lipid accumulation, hepatotoxicity, oxidation, and hepatocyte apoptosis, and activated mitochondrial mitophagy[47]
Human AD MSCs/ Human AD MSCs derived EVs	P4	Mouse	1 × 106 cells/mouse injected (i.v.)/ 1.0/2.5/5.0 μg injected (i.v.) at week 12	hADSCs or hADSC-EVs exhibited anti-inflammatory and anti-fibrotic effects in the NASH model[49]
Human UC MSCs derived CM	Not reported	Mouse	200 μL cells/mouse injected (i.v.) every 3 days for 2 months	hMSC-CM improved glucose tolerance, insulin sensitivity, and mitochondrial function, and alleviated liver dysfunction, lipid accumulation, inflammation, and apoptosis by upregulating SIRT1[50]
Human BM MSCs	Not reported	Mouse	1 × 107 cells/mouse injected (p.v.)	hMSCs decreased the inflammatory cytokines, LDL levels, IR, and oxidative stress in NAFLD with T2DM[51]
Mouse BM MSCs	P3	Mouse	0.5 × 106 cells/mouse injected (i.v.) at weeks 33 and 37	mMSCs administration prevented the onset of NASH in obese mice[52]
Murine CB MSCs	P5-8	Mouse	1 × 106 cells/mouse injected (i.v.) at weeks 6 and 7	mMSCs reduced weight loss, hepatic lipid peroxidation, steatosis, ballooning, lobular inflammation, and fibrogenesis in NASH[53]
Human BM MSCs	Not reported	Mouse	1.5 × 106 cells/mouse injected (i.v.) at day 42	Hepatocyte-like cells derived from hBMSCs attenuated liver lipid accumulation and inflammation, and enhanced the regenerative capacity of the liver in NASH[54]
Human UC MSCs	Not reported	Mouse	1 × 106 cells/mouse injected (i.v.) at week 10	hMSCs alleviated hepatic steatosis, inflammation, and fibrosis, and reversed microbiome and metabolome disorders[55]
Uncultured mouse AD MSCs	Not reported	Mouse	1 × 106/7.5 × 105 cells/mouse via splenic injection at weeks 24 and 26	u-ADSCs derived from a NASH mouse model and wild-type mice had similar effects in reducing inflammation and fibrosis in NASH[56]
Mouse AD MSCs	Not reported	Mouse	1 × 105 cells/mouse via splenic injected at weeks 4 and 8	mADSCs administration prevented the progression of NASH fibrosis by suppressing IL-17-mediated inflammation[57]
Human ESC MSCs derived EVs	Not reported	Mouse	1 and 10 μg/50 μL/mouse (i.p.) every other day for last 4 weeks	hMSC-EVs increased the number of anti-inflammatory M2 macrophages and suppressed fibrosis in NASH[58]
Human UC MSCs derived Exos	P4-7	Mouse	20 mg/kg body weight injected (i.v.) twice a week for 6 weeks	hUC-MSC-Exos regulated the anti-inflammatory phenotype of macrophages and reversed PPARα protein expression in liver cells[59]
Human AM MSCs derived EVs	Not reported	Rat	15 μg/kg body weight injected (i.v.) at weeks 3 and 4	AMSC-EVs alleviated inflammation and fibrosis in a NASH rat model[60]
Human SHEDs derived CM	P8-12	Mouse	0.5 mL cells/mouse injected (i.v.) once a week from week 10 to 12	SHED-CM treatment inhibited liver fibrosis, inflammation, and parenchymal cell apoptosis in NASH[61]
Human CB MSCs derived Exos with curcumin	Not reported	Mouse	15 μg/kg body weight injected (i.v.)	Exosomes derived from curcumin-preconditioned MSCs ameliorated NASH, protected against recurrence, and regulated inflammatory response, oxidative stress, and mitochondrial-dependent apoptosis[63]
Human UC MSC derived Exos	P3-4	Mouse	10 mg/kg body weight injected (i.v.) for last 4 weeks	hUC-MSC-Exos effectively reduced lipid deposition and improved liver function in an NAFLD mouse model via CAMKK1-mediated regulation of lipid homeostasis[64]
Rat AD MSCs stimulated with LPS	P3-5	Rat	1.5 × 106 cells/rat injected (i.v.) at week 8 for 6 weeks	ADSCs stimulated with LPS showed potential to alleviate NAFLD by reducing the expression of inflammatory genes and the levels of ROS[65]
Human UC MSCs	P5	Mouse	1.5 × 106 cells/mouse injected (i.v.) at week 32	hUC-MSCs administration alleviated obesity, improved glucose metabolism, and reduced hepatic steatosis, inflammation, and fibrosis in NASH[66]

MSCs: Mesenchymal stem cells; BM: Bone marrow; UC: Umbilical cord; AD: Adipose- derived; ESC: Embryonic stem cells; AM: Amniotic membrane; CM: Conditioned medium; CB: Cord blood; Exo: Exosome; EVs: Extracellular vesicles; SHED: Stem cells derived from human exfoliated deciduous teeth; LPS: Lipopolysaccharide; T2DM: Type 2 diabetes mellitus; i.v.: Intravenous; p.v.: Portal vein; i.p.: Intraperitoneal; MenSCs: Menstrual blood-derived stem cells; LDL: Low-density lipoprotein; Nrf2: Nuclear factor erythroid 2-related factor2; mADSCs: Mouse adipose-derived stem cells; ER: Endoplasmic reticulum; NASH: Non-alcoholic steatohepatitis; ROS: Reactive oxygen species; NAFLD: Non-alcoholic fatty liver disease; IL: Interleukin; LPS: Lipopolysaccharide; PPAR: Peroxisome proliferator-activated receptor.