Stimulating factors for regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells

Table 1 Growth factors, cytokines, and their effects on the differentiation of mesenchymal stem cells

Factors	Amount/types	Concentration	Cell dource	Results	Ref.
FGF	FGF-2	10 ng/ml	BM-PACs	FGF-2 did not lead to cell differentiation into a chondrogenic lineage	Endo et al[9]
	bFGF	5 ng/ml	SMSCs	Promoted SMSCs chondrogenic differentiation	Okamura et al[10]
	bFGF	0-40 ng/ml	UC-MSCs	bFGF did not alter osteogenic nor adipogenic differentiation potential	Ramasamy et al[12]
	bFGF	20 ng/ml	BMSCs	bFGF pretreatment inhibited osteogenic differentiation of BMSCs at early stage, promoted it in the medium phase, and maintained it in the later stage during osteogenic induction	Wang et al[13]
TGF-β	TGF-β3	10 ng/ml	SF-MSCs	Increased the expression levels of COL2A1, SOX9, ACAN, COL10A1	Jia et al[15]
	TGF-β	10 ng/ml	ADSCs	Promoted ADSCs chondrogenic differentiation but led to early hypertrophic maturation	Hesari et al[2]
	TGF-β1	1, 10, 20 or 50 ng/ml	BMSCs	Low concentration of TGF-β1 (1 ng/ml) promoted osteogenic differentiation of BMSCs while high concentration of TGF-β1 (10 to 50 ng/ml) significantly inhibited osteogenesis	Xu et al[17]
	TGF-β	5 ng/ml	BMSCs	Promoted osteogenic differentiation of BMSCs but suppressed the maturation of ostroblastic MSC differentiation at the last stage of osteogenic process	Igarashi et al[18]
	TGF-β3	10 μg/L	PDLSCs	Induced chondrogenesis	Choi et al[5]
IL	IL-6	100 ng/mL	BMSCs	Promoted BMSCs osteogenic differentiation	Xie et al[21]
	IL-17A	5-40 ng/ml	BMSCs	Promoted the neuronal-associated gene expression of BMSCs	Chen et al[24]
	IL-17	50 ng/mL	Mouse MSCs	Enhanced the osteogenic differentiation of mMSCs	Liao et al[22]
	IL-6	100 ng/mL	hMSCs	IL-6/soluble IL-6R promoted chondrogenic differentiation of MSCs	Kondo et al[20]
	IL-17A	50 ng/ml	BMSCs	Inhibited osteogenic differentiation of BMSCs	Wang et al[23]
	IL-22	10 ng/ml	MSCs	Upregulated osteogenic and adipogenic transcription factors	El-Zayadi et al[25]

FGF: Fibroblast growth factor; FGF-2/bFGF: Basic fibroblast growth factor; TGFβ: Transforming growth factor β; IL: Interleukin; BMSCs: Bone mesenchymal stem cells; BM-PACs: Bone marrow peri-adipocyte cells; ADSCs: Adipose-derived stem cells; hMSCs: Human mesenchymal stem cells; SMSCs: Synovial mesenchymal stem cells; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; SF-MSCs: Synovial fluid-derived mesenchymal stem cells; PDLSCs: Periodontal ligament stem cells; COL2A1: Collagen type II alpha 1 chain; SOX9: Sex-determining region Y-box 9; ACAN: Aggrecan protein; COL10A1: collagen type X alpha 1 chain.

Table 2 Micro RNA and their effects on the differentiation of mesenchymal stem cells

Amount/types	Expression	Cell source	Results	Ref.
micro-RNA-1286	Over expression	hMSCs	↓ Osteogenic differentiation	Zhou et al[27]
micro-RNA-223-3p	Low expression	BMSCs	↑ Osteogenic differentiation	Long et al[28]
micro-RNA-346-5p	Over expression	BMSCs	↓ Osteogenic differentiation	Zhang et al[29]
micro-RNA-21	Over expression	hucMSCs	↑ Osteogenic differentiation	Meng et al[4]
micro-RNA-130a	Over expression	BMSCs	↑ Osteogenic differentiation ↓ adipogenic differentiation	Lin et al[30]
micro-RNA-130b	Low expression	BMSCs	↑ Chondrogenic differentiation	Zhang et al[31]
micro-RNA-218	Over expression	SDSCs	↑ Chondrogenic differentiation during the eraly stage	Chen et al[32]
micro-RNA-495	Over expression	hMSCs	↓ Chondrogenic differentiation	Lee et al[33]
micro-RNA-30a	Over expression	BMSCs	↑ Chondrogenic differentiation	Tian et al[34]
micro-RNA-145	Low expression	ADSCs	↑ Endothelial differentiation	Arderiu et al[26]
micro-RNA-124	Over expression	ADSCs	↑ Neuronal differentiation	Mondanizadeh et al[35]
micro-RNA-10-5p	Low expression	BMSCs	↑ Myocardial differentiation	Li et al[36]
micro-RNA-499a-5p	Over expression	BMSCs	↑ Cardiomyogenic differentiation	Neshati et al[37]

↑: Increase; ↓: Decrease; hMSCs: Human mesenchymal stem cells; BMSCs: Bone mesenchymal stem cells; hucMSCs: Human umbilical cord mesenchymal stem cells; SDSCs: Synovium-derived mesenchymal stem cells; ADSCs: Adipose-derived stem cells.

Table 3 Physical stimuli and their effects on the differentiation of mesenchymal stem cells

Physical stimuli	Parameters	Cell source	Results	Ref.
EMF	1 mT, 15 Hz, 4 h/day	BMSCs	BMSCs pretreated with EMF exhibited stronger osteogenic and chondrogenic differentiation potential and weaker adipogenesis capacity	Tu et al[40]
	25, 50, 75Hz square and sinusoidal waveform EMF	BMSCs	EMF induced BMSCs differentiation to neuron cells in all treatment groups	Asadian et al[42]
	1 mT, 15 Hz, 4 h/day	Rabbit MSCs	EMF enhanced the osteogenic potential of MSCs	Wang et al[41]
	PEMF	MSCs	Brief exposure to low amplitude PEMFs enhanced the ability of MSCs to produce and secrete paracrine factors capable of promoting cartilage regeneration	Parate et al[43]
SMG	30 g for 72 h or 10 days	Adult rat MSCs	A shorter period of SMG promoted MSCs to differentiate into endothelial, neuronal and adipogenic cells. In comparison, a longer period of SMG promoted MSCs to differentiate into osteoblasts	Xue et al[48]
	10 rpm, 72 h, 0.001 G	BMSCs	Inhibited osteogenic differentiation of MSCs	Liu et al[47]
	30 rpm clinorotation, 3 d	Adult rat MSCs	Promoted the neuronal differentiation of rat MSCs	Chen et al[44]
	7 rpm, 21 d	hMSCs	Lowered the chondrogenic potential of hMSCs	Mayer-Wagner et al[50]
Microgravity	0.001 G	hMSCs	microgravity-cultured hMSCs showed a better ability to differentiate into osteoblasts and adipocytes compared to cells cultured under natural gravity conditions	Nakaji-Hirabayashi et al[46]]
Spare microgravity		hMSCs	Spare microgravity reduced the osteogenic differentiation of hMSCs and shifted the osteogenesis of hMSCs into adipogenesis, even during ostergenic induction	Zhang et al[49]
FSS	0.375 dyn/cm2, 2 h/d	BMSCs	Promoted osteogenesis-related genes and proteins in BMSCs	Jiang et al[54]
	0.06 dyn/cm2, 6 h/d	BMSCs	Proper FSS stimulation obviously enhanced BMSCs osteogenesis, while the expressions of osteogenic genes decreased with higher intensity of FSS	Jing et al[51]
	0.5, 0.8 Pa, 3 h/d	MSCs	Promoted MSCs ostegenesis	Jiao et al[55]
	3-7 dynes/cm2	hMSCs	Enhanced osteogenic differentiation	Zhao et al[52]
	4.2 dynes/cm2	hMSCs	FSS could lead to the osteogenic differentiation of hMSCs	Liu et al[53]
	ΔSS from 0 dyn/cm2 to 10 dyn/cm2	MSCs	Fast ΔSS (0–0′) profits the chondrogenic differentiation, while Slow ΔSS (0–2′) advances osteogenic differentiation	Yue et al[57]
	ΔSS from 0 dyn/cm2 to 10 dyn/cm2	MSCs	Fast ΔSS (0–0′) profits the chondrogenic differentiation, while Slow ΔSS (0–2′) advances osteogenic differentiation	Lu et al[56]
HP	10 MPa, 1 Hz, 4 h/d, 5 d/w, 3 w	BMSCs	HP promoted BMSCs chondrogenic differentiation	Steward et al[60]
	0-0.5 MPa, 0.5 Hz	hMSCs	HP promoted the differentiation of the hMSCs toward osteogenesis	Huang et al[59]
	270 kPa, 1 Hz, 1 h/d, 5 d/w, 3 w	BMSCs	HP promoted chondrogenic differentiation of BMSCs	Luo et al[64]
	100 psi	ADSCs	HP significantly increased osteogenic differentiation of AMSCs	Ru et al[65]
	90 kPa, 1 h	BMSCs	HP promoted chondrogenic differentiation of BMSCs	Zhao et al[61]
	90 kPa, 1 h	BMSCs	HP promoted the expression of marker genes for early osteogenic differentiation and chondrogenic differentiation of the BMSCs	Zhao et al[62]

BMSCs: Bone mesenchymal stem cells; EMF: Electromagnetic field; PEMF: Pulsed electromagnetic field; ADSCs: Adipose-derived stem cells; SMG: Simulated microgravity; hMSCs: Human mesenchymal stem cells; hucMSCs: Human umbilical cord mesenchymal stem cells; FSS: Fluid shear stress; ΔSS: Rate of fluid shear stress; HP: Hydrostatic pressure.

Table 4 Hypoxia and their effects on the differentiation of mesenchymal stem cells

Conditions	Cell source	Results	Ref.
Hypoxic culture (5%O2)	BMSCs	↑ Chondrogenic differentiation; ↑ adipogenic differentiation	Elabd et al[75]
Hypoxic culture (5.5%-6.5%O2)	Balb/c mouse clonal MSCs	↑ Osteogenic differentiation	Kim et al[74]
Hypoxic culture (50 μM CoCl2 simulation)	Mice MSCs	↑ Osteogenic differentiation	Yu et al[77]
Hypoxic culture (5%O2)	ADSCs	↑ Chondrogenic differentiation	Lee et al[76]
Hypoxic culture (1%O2)	PBMSCs	↑ Osteogenic differentiation	Yang et al[3]
Hypoxic culture (1%O2)	BMSCs	↓ Osteogenic differentiation; ↓ adipogenic differentiation; ↓ chondrogenic differentiation	Cicione et al[78]
Hypoxic culture (1%O2)	BMSCs	↑ Neuronal differentiation	Wang et al[80]
Hypoxic culture (1%O2)	BMSCs	↓ Osteogenic differentiation	Xu et al[72]
Hypoxic culture (2%O2)	ADSCs	↑ Tenocyte differentiation	Yu et al[73]
Hypoxic culture (2%O2)	ADSCs	↓ Osteogenic differentiation	Kim et al[79]
Hypoxic culture (2%O2)	BMSCs	↑ Osteogenic differentiation	Ciapetti et al[71]

↑: Increase; ↓: Decrease; BMSCs: Bone mesenchymal stem cells; MSCs: Mesenchymal stem cells; ADSCs: Adipose-derived stem cells; PBMSCs: Peripheral blood mesenchymal stem cells.

Table 5 Exosomes of different cell sources and their effects on the differentiation of mesenchymal stem cells

Source and kind	Specific cargo	Target	Results	Ref.
M1 macrophages-EVs	miRNA-21a-5p	BMSCs	↑ Osteogenic differentiation	Liu et al[104]
M0 macrophages-EVs		BMSCs	↓ Chondrogenic differentiation	Xia et al[105]
M1 macrophages-EVs		BMSCs	↑ Osteogenic differentiation; ↑ adipogenic differentiation; ↓ chondrogenic differentiation
M2 macrophages-EVs		BMSCs	↓ Chondrogenic differentiation
M2 macrophages-EVs	miRNA-5106	BMSCs;SIK2 and SIK3	↑ Osteogenic differentiation	Xiong et al[106]
M2 macrophages-EVs	miRNA-690	BMSCs	↑ Osteogenic differentiation; ↓ adipogenic differentiation	Li et al[107]
M0 macrophages-EVs		MSCs	↑ Osteogenic differentiation	Kang et al[108]
M1 macrophages-EVs	miRNA-155	MSCs	↓ Osteogenic differentiation
M2 macrophages-EVs	miRNA-378a	MSCs	↑ Osteogenic differentiation
M2 macrophages-EVs	miRNA-26a-5p	BMSCs	↑ Osteogenic differentiation; ↓ adipogenic differentiation	Bin-bin et al[109]
Macrophages-EVs		BMSCs	↓ Osteogenic differentiation	Song et al[103]
Monocytes-EVs		MSCs	↑ Osteogenic differentiation	Ekström et al[110]
Osteoclasts-EVs	miRNA-324	BMSCs	↑ Osteogenic differentiation	Liang et al[111]

↑: Increase; ↓: Decrease; EVs: Extracellular vesicles; MSCs: Mesenchymal stem cells; BMSCs: Bone mesenchymal stem cells; SIK2/SIK3: Salt-inducible kinase 2/3.