Stem Cell Applications and Tenogenic Differentiation Strategies for Tendon Repair

Table 1

Strategies in promoting tenogenic differentiation.

Treatment	Study type	Animal model	Cell source	Outcomes	References
Growth factors and bioactive proteins
TGF-β1	In vivo	Rat	—	Biomechanical strength↑	Arimura et al.; Am J Sports Med [59]
TGF-β2	In vitro	—	MSCs	Scx and Tnmd↑, N-cadherin and cadherin-11↓	Theodossiou et al.; Biochem Biophys Res Commun. [49]
TGF-β3	In vivo	Rat	—	Histological and biomechanical levels↑	Han et al.; Arthroscopy. [52]
CTGF	In vitro and in vivo	Rat	TSPCs	Col I, Tnmd, Scx, and Tnc↑ in vitro and promoting tendon healing with well-aligned collagen fibers in vivo	Lee et al.; J Clin Invest [58]
GDF-5	In vitro	—	BMSCs	Col I, Col III, Dcn, Scx, Tnc, and Tnmd↑	Ciardulli et al.; Int J Mol Sci [60]
GDF-6	In vitro and in vivo	Rat	BMSCs	Scx and Tnmd↑ in vitro and showing neotendon formation in vitro	Chai et al.; Chin Med J (Engl). [61]
GDF-6 and 7	In vitro	—	ESCs	Tnc, Col I, and III↑	Dale et al.; Tissue Eng Part A. [36]
GDF-8	In vitro	—	BMSCs	Col 1A, Scx, and Tnmd ↑	Le et al.; J Hand Surg Asian Pac Vol [62]
FGF-2	In vitro and in vivo	Rat	TSPCs	Scx and Col III↑ in vitro and enhancing tendon healing in vivo	Guo et al.; Biochem Biophys Res Commun [63]
FGF-8b	In vitro	—	ASCs	Scx, Tnmd, and Tnc↓, Col I and III↓	Otsuka et al.; Stem Cell Res [64]
TGF-β3 + BMP-12+ IGF1 + CTGF+FGF + AA	In vitro	—	MSCs	Scx↑ (induced by TGF-β3) and decorin↑ (induced by BMP-12, FGF and AA)	Perucca Orfei et al.; Int J Mol Sci [65]
Wnt ligands	In vitro	—	BMSCs	Tnmd, decorin, and Fmod↑	Miyabara et al.; J Equine Sci. [66]
PRP	In vitro	—	Paratenon-derived cells	Scx and col I↑	Imai et al.; Sports Health [67]
Gene modification
Transfection with BMP-12 and CTGF	In vitro and in vivo	Rat	TSPCs	Tnc, Col I and III↑ in vitro and presenting better outcome on histology level in vivo	Xu et al.; J Biomech [68]
Transfection with Scx	In vitro	—	BMSCs	Tnmd, Col I and several tendon-related matrix proteoglycans↑	Alberton et al.; Stem Cells Dev [69]
Transfection with Mkx	In vitro	—	BMSCs	Tnmd, Tnc and Col I↑	Otabe et al.; J Orthop Res [70]
Transfection with Egr1	In vitro and in vivo	Rabbit	TSPC	Scx and Tnmd↑ in vitro and promoting rotator cuff repair in vivo	Tao et al.; Cell Physiol Biochem [71]
MiR-378a	In vitro and in vivo	Mice	TSPCs	Scx, Mkx, Fmod, Thbs4, Col I and III↓ in vitro, and Thbs4, Col I↓ in vivo	Liu et al.; Stem Cell Res Ther [72]
lncRNA H19	In vitro and in vivo	Mice	TSPCs	Sxc, Mkx, Tnmd, Fmod, Dcn, and Col I↑ and enhancing tendon healing in vivo	Lu et al.; FASEB J [73]
Biomaterials
Tendon ECM-supplemented scaffold	In vitro	—	ASCs	Scx, Tnmd, and Tnc↑	Yang et al.; Biomaterials [74]
Nanofiber and microfiber scaffolds	In vitro	—	Tendon fibroblasts	Cell number, total collagen and proteoglycan production↑ in nanofibers; Tnmd, Col I, III, and V↑ in microfibers	Erisken et al.; Tissue Eng Part A [75]
Mechanical stimulation
Dynamic stretch+ woven nanofibrous PCL scaffold	In vitro	—	ASCs, tenocytes, and HUVEC	Scx, Tnmd, Tnc, VEGFA, and Col I and III↑, as well as the total collagen content↑	Wu et al.; Acta Biomater [76]
Uniaxial loading on 3D constructs	In vitro	—	TSPCs	Scx, Mkx, Tnmd, Col I I, and neotendon formation	Wang et al.; FASEB journal [77]
Cyclic tensile strain	In vitro	—	TSPCs	The expression of Col I, TNc, Tnmd, and Scx was most apparant at 0.5 Hz frequency with the same amplitude and at 4% amplitude with the same frequency	Xu et al.; Biomed Res Int [78]

Abbreviations: TSPCs: tendon stem/progenitor cells; BMSCs: bone marrow stromal cells; ASCs: adipose-derived mesenchymal stem cells; ESCs: embryonic stem cells; MSCs: mesenchymal stem cell; HUVEC: human umbilical vein endothelial cells.