Effect of metformin on stem cells: Molecular mechanism and clinical prospect

Table 1 Summary of effect of metformin on stem cells and suggested mechanisms

Role of metformin	Stem cell type(s)	Suggested mechanism(s)	Ref.
Promoting osteogenic differentiation	BMPC; ADSC; UC-MSC; iPSC-MSC	LBK1/AMPK activation	[20-23]
	BMSC	AMPK activation-Runx2 (serine 118)	[26]
	MC3T3-E1	AMPK/Gfi1/OPN axis; SIRT-6/NF-κB	[12,24]
	hBMSC	Twist1 inhibition; GSK3β/β-catenin/Wnt signaling pathway	[19,25]
	PDLSC	AKT/Nrf2	[27]
	ADSC; PDLSC; hDPSC	None	[8,11,32,33]
Promoting neuronal differentiation	NPC	aPKC/CBP	[35]
	hBMSC	AMPK activation	[36]
	NPC	AMPK/aPKC/CBP signaling pathway	[37]
	hiPSC-NSC	None	[17]
Promoting myogenic differentiation	Satellite cell	RPS6-mTOR	[14]
	C2C12	ERK; AMPK (AMPKα1)/HDAC5	[40,41]
	Muscle progenitor cell	AMPK	[39]
Inhibiting adipogenic differentiation	MC3T3-E1	AMPK/Gfi1/OPN axis	[24]
	MSC	AMPK/mTOR/p70S6K	[44]
	ADSC; PDLSC; BMSC; BMPC	None	[13,27,42,43,46]
Inhibiting chondrogenic differentiation	ATDC-5	AMPK	[47]
Gastric PC differentiation	Gastric EPC	AMPK	[50]
Regulating stem cell aging and rejuvenating regeneration	HMSC	Nrf2/GPx7	[59]
	ISC	AKT/TOR/Atg6-related pathway; AKT/mTOR pathway	[62-64]
	Satellite cell	mTOR /p70S6	[14]
	OPC	AMPK activation	[68]
Inhibiting CSCs	CSC	Hedgehog, Wnt, and TGF-β pathways	[72]
	Glioblastoma CSC	C1CL1	[74]
	Colorectal cancer CSC	MIF/CD74 axis	[77]
	Breast CSC	MiR708/CD47 axis	[81]
	CSC	None	[73,76,82]
Improving EPC functions and angiogenesis	EPC	AMPK/eNOS/NO signaling pathway; AMPK/mTOR/autophagy pathway; AMPK/mTOR/p70S6K pathway	[89,90]
Antioxidant	ADSC, C2C12	ROS&NO reduction/SOD activation	[13,40,99]
	PDLSC	AKT-Nrf2 signaling pathway	[27]
	HMSC	Nrf2/GPX7	[59]
	hNSC	AMPK activation	[98,100,102]
Anti-inflammatory	hNSC	AMPK/(IKK/NF-κB)	[15]
	rabbit AFSC	HMGB1	[104]
Immunomodulatory potential	ADSCs	AMPK/mTOR/STAT-1 signaling pathway	[107]

BMPC: Bone marrow progenitor cells; ADSC: Adipose-derived stem cells; UC: Ulcerative colitis; iPSC: Induced pluripotent stem cell; MSC: Mesenchymal stem cell; LKB1: Liver kinase B1; AMPK: Adenosine 5′-monophosphate-activated protein kinase; BMSC: Bone marrow stromal cell; Runx2: Runt-related transcription factor 2; Gfi1: Growth factor independence-1; OPN: Osteopontin; NF-êB: Nuclear factor kappa-B; GSK3â: Glycogen synthase kinase 3â; PDLSC: Periodontal ligament stem cell; Nrf2: Nuclear factor E2-related factor 2; DPSC: Dental pulp stem cells; NPC: Neural precursor cell; aPKC: Atypical protein kinase C; CBP: CREB-binding protein; hiPSC: Human induced pluripotent stem cell; NSC: Neural stem cell; RPS6: Ribosomal protein S6 kinase; mTOR: Mammalian target of rapamycin; HDAC5: Histone deacetylase 5; MSC: Mesenchymal stem cell; EPC: Endothelial progenitor cell; HMSC: Human mesenchymal stem cell; GPx7: Glutathione peroxidase 7; ISC: Intestinal stem cell; OPC: Procyanidins oligomers; CSC: Cancer stem cell; TGF-β: Transforming growth factor-β; MIF: Macrophage migration inhibitory factor; eNOS: Endothelial nitric oxide synthase; IKK: Inhibitory NF-κB kinase; hNSC: Human neural stem cell; AFSC: Amniotic fluid or stem cells; HMGB1: High mobility group box 1; STAT-1: Statim-1; SIRT-6: Silent information regulator-6.