Innovative mesenchymal stem cell treatments for fatty liver disease

Table 1 Mesenchymal stem cell treatments for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and alcohol associated liver disease

Ref.	Cell source	Secretome	Model	Disease	Function and mechanism
Du et al[15]	MenSCs	HGF	Mouse	NAFLD	Rnf186 regulated glucose and lipid metabolism through the AMPK/mTOR pathway
					HGF decreased the expression of hepatic Rnf186
Wang et al[13]	Mouse BM-MSCs	-	Mouse	NAFLD	Suppressed the activation of CD4+ T cells
Hu et al[9]	Human UC-MSCs	-	Mouse	NASH	Alleviated obesity, glucose metabolism, hepatic steatosis, inflammation, and fibrosis
					Regulated lipid metabolism and the PPAR signaling pathway
Yang et al[11]	Human UC-MSCs	-	Mouse	NASH	Alleviated hepatic steatosis, inflammation, and fibrosis
					Reversed the microbiome and metabolome disorders
Li et al[14]	Rat BM-MSCs	-	Mouse/HepG2 cells	NAFLD	Regulation of ER stress and the calcium homeostasis via SERCA
Bi et al[16]	BM-MSCs	Mitochondria	Mouse/hepatocytes	NAFLD	Mitochondrial transfer from BMSCs rescued dysfunction mitochondria
Nickel et al[17]	Human BM-MSCs	Mitochondria	Mouse	NASH	Resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes
Domingues et al[19]	Antioxidant-upregulated human AD-MSCs	-	Mouse	Diet-induced obese	Reduced oxidative stress post-antioxidant-upregulated MSC delivery, intraperitoneally, and reduced systemic inflammation and fat accumulation in the liver
Winkler et al[18]	Human BM-MSCs	-	Mouse	NASH	Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver
Cai et al[32]	BM-MSCs	-	Mouse	Chronic alcoholic hepatitis	Through the PI3K/NF-κB and PI3K/mTOR pathways
					Modulation of natural killer B cells and follicular helper T cells
Huai et al[37]	Human UC-MSCs	FGF21	Mouse	ALD	Enabled macrophages to exhibit anti-inflammatory inclination
Li et al[38]	Lysophosphatidic acid receptors and sphingosine-1-phosphate receptors-co-treated human AD-MSCs	-	Mouse	ALD	Ameliorated histological damage, oxidative stress, inflammation, fibrosis, and lipid metabolism dysfunction, and enhanced alcohol metabolizing enzyme activity
Ge et al[39]	BM-MSCs/BM-MSCs pre-activated with TLR3	-	Mouse	Chronic-binge alcohol	Protection against alcohol-induced intestinal and hepatic injury and immune dysfunction
Hernandez et al[40]	Human UC-MSCs	-	Mouse	Alcohol binge drinking	Activated stem cells resulted in marked improvement in survival and in recovery of hepatic chemistries
Chung et al[34]	Sk-MSCs	HGF	Mouse/human colonic Caco-2/tc7 cells	Alcoholic liver damage	Reduced inflammatory responses in the liver and gut
Wan et al[35]	BM-MSCs	TSG-6	Mouse	Alcoholic hepatitis	Secreted TSG-6 to inhibit STAT3 activation and to reduce liver injury
Wan et al[33]	BM-MSCs	-	Mouse	Alcoholic hepatitis	Inhibited hepatic neutrophil and macrophage infiltration, and alleviated oxidative stress

MenSCs: Menstrual-derived endometrial stem cells; HGF: Hepatocyte growth factor; NAFLD: Non-alcoholic fatty liver disease; BM-MSCs: Bone marrow mesenchymal stem cells; UC-MSCs: Umbilical cord mesenchymal stem cells; NASH: Non-alcoholic steatohepatitis; AD-MSCs: Adipose-derived mesenchymal stem cells; ALD: Alcohol associated liver disease; Sk-MSCs: Skeletal muscle satellite cell-derived mesenchymal stem cells; SERCA: Sarco(endo)plasmic reticulum Ca(2+)-ATPase; AMPK: AMP-activated protein kinase; PI3K: Phosphoinositide 3-kinase; mTOR: Mechanistic target of rapamycin; NF-κB: nuclear factor kappa B; TSG-6: Tumor necrosis factor-stimulated gene-6; STAT3: Signal transducer and activator of transcription 3; FGF21: Fibroblast growth factor 21; TLR3: Toll-like receptor 3; PPAR: Peroxisome proliferator-activated receptor; ER: Endoplasmic reticulum; BMSC: Bone marrow mesenchymal stem cell; MSC: Mesenchymal stem cell.

Table 2 Mesenchymal stem cell derivatives for treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

Ref.	Cell source	Secretome	Model	Disease	Function and mechanism
Kang et al[24]	Human UC-MSC-EV	-	Mouse/HepG2 and AML12 cells	NASH	Nrf2/NQO-1 antioxidant signaling pathway
Yang et al[25]	Human UC-MSC-EV	CAMKK1	Mouse/hepatic cells	NAFLD	CAMKK1-mediated lipid homoeostasis regulation
Chen et al[30]	MSC-sEV	RNF31	Mouse	NAFLD	Regulation of mitochondrial homeostasis
Du et al[26]	Human UC-MSC-Exo	MiRNA-24-3p	Mouse/hepatocytes	NAFLD	MiR-24-3p directly targeted Kelch-like ECH-associated protein 1, and suppressed its expression
					Restrained lipid accumulation, ROS generation, and inflammation
Niu et al[27]	AD-MSC-EV	MiRNA-223-3p	Mouse/hepatocytes	NAFLD	MiR-223-3p displayed suppressive effects on lipid accumulation and liver fibrosis through E2F1 inhibition
Cheng et al[28]	Human UC-MSC-Exo	MiRNA-627-5p	Rat/L-02 cells	NAFLD	MiR-627-5p improved glucose and lipid metabolism and alleviated liver damage by repressing FTO expression
El-Derany et al[29]	BM-MSC-Exo	MiRNA-96-5p	Mouse	NASH	Caspase-2 signaling inhibition
Tawfeek and Kasem[20]	Curcumin-preconditioned MSC-Exo	-	Mouse/HepG2 cells	NASH	Regulated inflammatory, oxidative stress, and mitochondrial-dependent apoptosis-associated ASK-JNK-BAX genes
Kim et al[21]	Pan-peroxisome proliferator-activated receptor agonist-primed induced MSC-EV	-	Mouse	NASH	Reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation
Zhang et al[23]	MSC-sEV	-	Mouse	NASH	Polarized pro-fibrotic M2 macrophages without exacerbating liver fibrosis
Yang et al[31]	MSCs conditional medium	-	Mouse/L-02 cells	NAFLD	Improved mitochondrial function and alleviated inflammation and apoptosis by regulating SIRT1

UC-MSC-EV: Umbilical cord mesenchymal stem cells extracellular vesicle; NASH: Non-alcoholic steatohepatitis; NAFLD: Non-alcoholic fatty liver disease; MSC-sEV: Mesenchymal stem cells small extracellular vesicle; UC-MSC-Exo: Umbilical cord mesenchymal stem cells exosome; AD-MSC-EV: Adipose-derived mesenchymal stem cells extracellular vesicle; BM-MSC-Exo: Bone marrow mesenchymal stem cells exosome; Nrf2: Nuclear factor erythroid 2-related factor 2; NQO-1: NAD(P)H quinone oxidoreductase-1; CAMKK1: Calcium/calmodulin-dependent protein kinase 1; ROS: Reactive oxygen species; MSC: Mesenchymal stem cell.