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.