The Functions and Mechanisms of Tendon Stem/Progenitor Cells in Tendon Healing

Table 3

Factors that induce nontendon lineage differentiation of TSPCs.

Factors	Stem cell source	Outcomes	Conclusion	Reference
P16 (gene)	Human	Inhibits tenogenic differentiation of TSPCs	Aging marker gene P16 via microRNA signaling pathways	[77]
Extracellular matrix (ECM)	Mouse	Osteogenic differentiation	Double knockout of ECM with biglycan and fibronectin induces differentiation of TSPC into osteoblasts and a reduction in collagen Ⅰ	[13]
Mechanical loading	Sprague-Dawley rats	BMP-2 mRNA, ALP↑	Promoting osteogenic differentiation by upregulating BMP-2 expression following repetitive stretch loading	[78]
Mechanical stimulation (8% double axis MS)	Human	Fibromodulin, lumican, and versican↑ Collagen I↑ MMP9, 13, and 14↑	Mechanical stimuli are mediated through ERK1/2 and p38, which were significantly activated in 8% biaxial-loaded TSPC	[79]
Mechanical stimulation (8% MS)	(SD) rats	Adipogenic, osteogenic, and chondrogenic differentiation SOX9, CollagenⅡ↑	Mechanical loading activates mTOR signaling in TSPCs and results in their differentiation by nontendon lineage	[80]
Uniaxial mechanical stimulation (8% MS)	Rats	Osteogenic differentiation RUNX2, Dlx5, Alpl, and Collagen I↑ Wnt5a, Wnt5b, and P-JNK protein↑	UMT induced the osteogenic differentiation of rTDSCs via the Wnt5a/Wnt5b/JNK signaling pathway	[81]
Uniaxial Mechanical stimulation (2% MS)	Rats	Osteogenic differentiation RUNX2 mRNA, Collagen I, Alpl mRNA↑ Wnt5a↑	UMT-induced osteogenic differentiation of rTDSCs via the Wnt5a-RhoA pathway, which might contribute to ectopic ossification in tendon tissue due to mechanical loading	[82]
PGE2	Rats	Adipogenic and osteogenic differentiation TSPC proliferation↓	TSPCs are induced by PGE2 to differentiate into adipocytes and osteocytes, which in turn lead to adipose accumulation and calcification in tendinopathy	[83]
PGE2 (0–10 ng/ml)	Rabbit patellar	Adipogenic and osteogenic differentiation	PGE2 not only prevents the proliferation of TPSCs, but also induces it to differentiate into adipocytes and osteoblasts, which in turn leads to degenerative changes in the tendon	[84]
IL-6	SD female rat	Scx, Tnmd, Egr-1↓ Fmod, Lum, Collagen I, Collagen Ⅲ↓ cell proliferation↑	IL-6 stimulates TPSCs proliferation but inhibits their tenogenic differentiation	[85]
IL-10	SD rats	Collagen I, CollagenⅢ↓ Scx, Tnmd↓ Egr-1↓ Cell proliferation of TSPCs↑	IL-10 promoted the proliferation and migration of TDSCs, but also inhibited its tenogenic differentiation	[86]
IL-1β	CD-1 mouse	Egr-1, Collagen I, Collagen Ⅲ↓ Mkx, MMP13↑	IL-1β irreversibly inhibits tenogenic differentiation of inTPCs	[87]
BMP-2	SD rats	GAG, Acan↑Dcn, Bgn, Fmod ↓	BMP-2 promoted osteogenic, adipogenic, and chondrogenic differentiation but inhibited tenogenic marker expression of TSPCs	[88]
CTRP3	Mouse	PG↑, Col2a1, Acan, Fn1, and SOX9↑ Scx, Mkx, Tnmd↓	CTRP3 is significantly increased in loading tendinopathy and it stimulates chondrogenesis and inhibits tenocyte production	[89]
High glucose	Rats	Scx, Tnmd, Collagen I↓ cell proliferation↓	High glucose could inhibit proliferation, induce cell apoptosis, and suppress the tendon-related markers expression of TDSCs in vitro	[90]
Nesfatin-1	(SD) rats	Osteogenic differentiation Scx, Mkx, Tnmd↓ Collagen I, ALP, and RUNX2 ↑	Nesfatin-1 accelerated the pathogenesis of HO through the mTOR pathway in vivo	[91]
Dex	Human patellar tendon	Collagen I↓ PPARγ, SOX9↑	Higher concentrations of Dex treatment induced hTSPC differentiation into nontenocytes (adipocytes and chondrocytes)	[92]
Dexamethasone	(SD) rats	Collagen I and Tnmd mRNA↓ Scx mRNA↓	Dexamethasone inhibits the differentiation of TSPCs to tenocytes by inhibiting the Scx gene	[93]
Celecoxib	Male C57 mouse	Scx, Egr1 mRNA↓ Tnmd, Bgn, Dcn, Fmod, Tnc, and Eln mRNA↓ cell number n.a	Celecoxib inhibits tenocytic differentiation of TSPCs but has no effects on cell proliferation	[94]
Diabetes mellitus (DM)	(SD) rats	Osteogenic and chondrogenic differentiation OPN, OCN, SOX9, Collagen Ⅱ↑ BMP-2, ALP↑ collagen Ⅰ, Tnmd↓	TPSCs in diabetic rats not only have reduced ability to proliferate, but also have higher osteochondral formation and lower tenogenic differentiation	[95]
Cholesterol	Rats	LC3-II↑, ROS↑ CAT, NOX4↑	High cholesterol induces apoptosis by up-regulating ROS in TPSCs to activate the FOXO1 pathway, thereby causing tendinopathy	[96]
MiR124	Human	Collagen Ⅰ, Ⅱ↓ Fmod, Dcn↓	MiR124 hampers collagen production in TSPCs by inhibiting the expression of Egr	[97]
Wnt/β-catenin signaling	(SD) rats	Scx, Mkx, and Tnmd↓ Bglap, Alpl↑	Wnt/β-catenin signaling is a repressor for tenogenic gene expressions	[98]
ERK1/2 signaling pathway (normoxic (20% O2) conditions)	Rats	ALP activity↑ gene (ALP, osteocalcin, collagen I, and RUNX2) ↑	ERK1/2 signaling pathway is involved in the osteogenic differentiation of TSPCs under normoxic conditions	[99]

Note: ↑, significant increase; ↓, significant decrease. n.a, not affected; TSPCs, tendon stem/progenitor cells; MMP-9, matrix metalloproteinase-9; MMP-13, matrix metalloproteinase-13; MMP-14, matrix metalloproteinase-14; SOX9, SRY-box9; rTDSCs, rat t tendon-derived stem cells; PGE2, prostaglandin E2; IL-6, interleukin-6; IL-10, interleukin-10; Scx, scleraxis; Tnmd, tendmodulin; Mkx, Mohawk; HO, heterotopic ossification; ALP, alkaline phosphatase; RUNX2 ↑, Runt-related transcription factor 2; OPN, osteopontin; OCN, osteocalcin; BMP-2, bone morphogenetic protein 2; Dcn, decorin; Acan, aggrecan; Fmod, fibromodulin; GAG, glycoaminoglycans; Alpl, alkaline phosphatase.