Small molecules for mesenchymal stem cell fate determination

Table 1 Selected Small molecules in controlling mesenchymal stem cells fate

Small molecules	Origin/Natural source	Effect	Pathway/Targets	Experimental model and dose	Comments	Ref.
5-azacytidine	Synthetic	Anti-adipogenic	Inhibit DNA methyltransferase	ST2 cells (0.5 μmol/L)	Reduce expression level of PPARγ, aP2, FAS and C/EBPα	[13,8]
8-HUDE	Synthetic	Anti-adipogenic	Activate HO-1 pathway	Human BM-MSCs (1 μmol/L)	Reduce expression level of Fas, Pparγ, and Cebpα	[132]
Albiflorin	Paeonia lactiflora	Beige-Adipoinductive	Activate AMPK, PI3K/AKT/mTOR pathways	Human AD-MSCs (5, 10, 20 μmol/L)/ HFD mice (5 mg/kg per day, in an unknown solvent, orally)	Cell viability decrease when AF exceeds 20 μmol/L. Induce expression of thermogenic marker Ucp1.	[126]
Arctigenin	Arctii fructus, Forsythia fruit	Anti-adipogenic	Activate AMPK pathway	Human AD-MSCs (10, 50, 100 μmol/L)/HFD mice (50 mg/kg per day, in 10% DMSO, orally)	Cell viability was not affected by ARC.	[125]
Atractylenolides	Atractylodis macrocephalae	Chondroinductive	Activate Shh pathway	Rat BM-MSCs (10, 100, 500 μg/mL)	Induce Sox9 collagen type II and aggrecan expression	[149]
AUDA	Synthetic	Anti-adipogenic	Activate HO-1 pathway	Human BM-MSCs (1 μmol/L)	Reduce expression level of Fas, Pparγ, and Cebpα	[132]
Baicalin	Scutellaria baicalensis	Osteoinductive	Activate Wnt pathway	Rat BM-MSCs (0.1, 0.5, 1, 5, 10, 50 μmol/L)/ Radix Scutellariae extract (2 and 50 mg/kg per day, orally)	Enhance ALP activity	[54,55]
Cordycepin	Cordyceps militaris	Osteoinductive	Activate Wnt pathway	Human BM-MSCs with H2O2 treatment (1, 5, 10, 20, 40, 80 μg/mL)/ Human BM-MSCs with ethanol treatment/ rat alcohol-induced osteonecrosis of the femoral head model (10 mg/kg per day in saline intraperitoneal)	Induce osteogenic markers osteopontin and collagen type I expression	[59,61]
Cyanidin-3-O-glucoside	Black rice	Anti-adipogenic	Activate Wnt pathway	C3H10T1/2 cells (black rice extract 10, 20, 40, and 80 μg/ mL)/ HFD mice (black rice extract 10% corn oil and 90% water, 100 mg/kg per day, orally)	Induce Wnt-specific target genes such as Axin2, Wisp2, and Cyclin d1	[114]
Dihydroartemisinin	Artemisia apiacea	Anti-chondrogenic	Activate Notch pathway	C3H10T1/2 cells (1, 10, 50, 200, 300 μmol/L)	Suppress Sox9, COMP and Col2a1 expression	[151]
Er-Xian Decoction extracts	Er-Xian Decoction	Osteoinductive	Activate MAPK/ERK pathway	OVX mice (30g/kg per day, orally)/ Mice BM-MSCs (isolated from OVX and treated mice)	Elevate ALP activity.	[94]
Ethanol	Alcohol	Anti-osteogenic	Inhibit TGFβ pathway	MSCs (25 mmol/L)/ Tibial fracture mice (20% in saline, intraperitoneal)	Inhibit Col I and Sox9 expression	[62]
Genistein	Soybean	Osteoinductive	Activate BMP pathway	Human BM-MSCs (10 -0.01 μmol/L, MAX at 1 μmol/L)	Induce Runx2 and osteocalcin expression, inhibit BMP pathway inhibitor SMAD6, 7	[44]
Ginkgo biloba extract	Ginkgo biloba	Adipoinductive Osteoinductive	Activate BMP and Wnt pathways	Mouse BM-MSCs (50, 100, 150, 200, 400 μg/mL)/ human BM-MSCs (25, 50, 70, 100)	Induce Runx2, Col 1a1 and BMP-2 experssion	[64,65]
Ginkgolic acid	Ginkgo biloba	Adipoinductive	Inhibit sumoylation	Mouse BM-MSCs (50 μmol/L)	Promote adipogenic commitment and inhibit adipocyte terminal maturation.	[136]
Icariin	Herba epimedii	Osteoinductive	Activate MAPK, BMP, WNT and PI3K/AKT pathway	MC3T3-E1 cells, rat BM-MSCs (0.0001, 0.001, 0.01, 0.1, 1, 10 μmol/L; 5, 10, 20, 40 μmol/L)/ OVX rats (150 mg/kg in saline, orally)	Induce Runx2, BMP4, and Col I expression	[88,89,90,92]
Isorhamnetin	Sea buckthorn	Anti-adipogenic	Activate Wnt pathway	Human AD-MSCs (1, 25 μmol/L)	Downregulate Wnt antagonist Sfrp1 and Dkk1	[113]
Medicarpin	Medicago truncatula	Beige-Adipoinductive	Activate AMPK pathway	C3H10T1/2 cells (10μmol/L)	Induce expression of thermogenic marker Ucp1.	[121]
		Osteoinductive	Activate Wnt and Notch pathways	OVX mice (1 mg or 10 mg/kg per day, orally)/ OVX + Drill hole mice (0.5, 1 mg/kg per day, orally)	Induce Runx2, Osteocalcin and TGF-β expression	[57,58]
Naringin	Rhizoma Drynariae	Osteoinductive	Activate AMPK and AKT pathway	Human BM-MSCs (1, 10, 100 μg/mL)/ OVX mice (0, 0.5, 1, 5 and 10 mg/kg per day, orally)	Induce osteocalcin, collagen type I, osteopontin and ALP expression.	[81,82]
N-methyl pyrrolidone	Synthetic	Anti-adipogenic	Inhibit Brd4	Human BM-MSCs (5, 10 mM)/ OVX mice (10.5 mM/100 g/wk, intraperitoneal injection)	Reduce PPARγ expression level	[140]
Oleanolic acid	Glossy privet	Osteoinductive	Activate Notch pathway	Rat BM-MSCs (1, 10, 100 μmol/L) / OVX mice (2 wks, 3 mo, dissolve in normal saline, 20 mg/kg per day, orally)	KEGG analysis on differential gene patterns	[69]
Peonidin-3-O-glucoside	Black rice	Anti-adipogenic	Activate Wnt pathway	C3H10T1/2 cells (black rice extract 10, 20, 40, and 80 μg/ mL)/ HFD mice (black rice extract in 10% corn oil and 90% water, 100 mg/kg per day, orally)	Induce Wnt-specific target genes such as Axin2, Wisp2, and Cyclin d1	[114]
Plastrum testudinis extracts	Plastrum testudinis	Osteoinductive	Activate PI3K/AKT pathway	Rat BM-MSCs (0.03, 0.3, 3, 30, 300 μg/mL)/ Dexamethasone induced osteoporosis rat (30 mg/kg per day, subcutaneous injection)	Induce β-catenin, Runx2 and osteocalcin expression	[76,77]
Platycodin D	Platycodi radix	Anti-adipogenic Beige-Adipoinductive	Activate AMPK pathway	Human AD-MSCs (0.5-5 μmol/L)/ db/db mice (2, 5 mg/kg per day)	Suppress adipogenic genes, such as Pparγ, Cebpα, Fabp4, Adipoq, and Resistin	[127]
Psoralen	Psoralea corylifolia	Anti-adipogenic Osteoinductive	Activate Notch pathway	Rat BM-MSCs (? μmol/L) / OVX mice (2 wks, 3 mo, dissolve in normal saline, 20 mg/kg per day, orally)	KEGG analysis on differential gene patterns	[68]
Psoralidin	Psoralea corylifolia	Anti-adipogenic Osteoinductive	Activate PI3K/AKT pathway	OVX rat (in sesame oil, 10 mg/kg per day, orally)	Promote osteogenic differentiation of BM-MSCs isolated from the treated OVX mice	[78]
Resveratrol	Wine, grape	Osteoinductive	Activate MAPK/ERK pathway	Human BM-MSCs (0.01, 0.1, 1, 10, 100 μmol/L)	Induce Runx2, osterix and osteocalcin expression	[96]
Risedronic acid	Synthetic	Anti-adipogenic	Inhibit PI3K/AKT/mTOR pathway	Human BM-MSCs (1, 5, 10, 25 μmol/L)	Inhibit mTOR1 downstream effector S6 phosphorylation	[118]
Salvianolic acid B	Salvia miltiorrhiza	Osteoinductive	Activate MAPK/ERK pathway	Rat BM-MSCs (50, 100, 500, 1000 nmol/L)/ Steroid induced osteoporotic rat (40, 80 mg/kg per day)	Enhance ALP activity and osteocalcin expression	[101,102]
SKL2001	Synthetic	Osteoinductive	Activate Wnt pathway	ST2 cells (5, 10, 30 μmol/L)	Stabilize β-catenin without affecting expression level	[63]
T63	Synthetic	Anti-adipogenic Osteoinductive	Activate BMP and Wnt pathway	C3H10T1/2 (1-40 μmol/L)/ OVX mice (5 mg/kg and 20 mg/kg, orally)	Induce Runx2, Bglap and, Spp1 expression.	[47]
Tithonia diversifolia extracts	Tithonia diversifolia	Anti-adipogenic	Activate HO-1 pathway	Human AD-MSCs (175 μg/mL)	Oil red staining quantitatively decrease in a dosage-dependent manner	[130]
Tricin	Rice bran	Osteoinductive	Activate Wnt pathway	Human AD-MSCs (5, 10, 15, 20, 25 μmol/L)	Induce bone sialoprotein, osteocalcin, ALP, Runx2, Col I, osterix, osteopontin	[53]

8-HUDE: 12-(3-hexylureido) dodec-8(Z)-enoic acid; ALP: Alkaline phosphatase; AUDA: 12-(3-adamantan-1-yl-ureido)-dodecanoic acid; AD-MSCs: Adipose-derived mesenchymal stem cell; BM-MSCs: Bone marrow mesenchymal stem cell; HFD: High-fat diet; OVX: Ovariectomy; Runx2: Runt-related transcription factor 2; TGF-β: Transforming growth factor beta; Col I: Type I collagen; KEGG: Kyoto encyclopedia of genes and genomes; AMPK: AMP-activated protein kinase.