Table 1 Summary of developmental tendon models
Developing Tendon Characteristics | Model Characteristics | Model Outcomes | References |
|---|---|---|---|
High cell density and low collagen content (Ansorge 2011) [26] (Chaplin 1975) [27] (Richardson 2007) [28] (Schiele 2015) [29] | Self-assembled cellular fibers | Upregulated expression of scleraxis and tenomodulin with loading; potential for scaffold-free, cellular self-assembly for single tendon fibers | Mubyana 2018 [34] Schiele 2013 [35] |
Embryonic tendon cells in fibrin gels | Upregulated tendon genes and collagen synthesis; improved tendon formation in fibrin gel vs collagen gel models | Kalson 2010 [36] Kapacee 2010 [33] Yeung 2015 [37] Breidenbach 2015 [38] | |
Cell-cell junction proteins (Cadherin-11 & N-Cadherin) (Richardson 2007) [28] | Chick tendon explants, fibroblasts, and mouse MSCs | Possible regulators of early tendon tissue formation; N-cadherin and cadherin-11 levels decreased with tenogenic induction | Richardson 2007 [28] Schiele 2013 [35] Theodossiou 2019 [39] |
TGFβ2&3 (Pryce 2009) [21] (Kuo 2008) [30] | Mouse embryonic tendon progenitor cells and fibroblasts, and MSCs | TGFβ2 increased scleraxis and tenomodulin expression | Pryce 2009 [21] Brown 2014 [40] Brown 2015 [41] Havis 2014 [42] Havis 2016 [43] Chien 2018 [44] |
Mouse MSCs | TGFβ2 increased scleraxis and tenomodulin production; decreased N-cadherin and cadherin−11 production | Theodossiou 2019 [39] | |
Human BM-MNCs and MSCs in fibrin gels | TGFβ3 increased collagen fibril synthesis, and upregulated TGFβ3, Col I, and Smad2 | Kapacee 2010 [33] | |
Scleraxis and mohawk (Schweitzer 2001) [18] (Liu 2015) [31] (Otabe 2015) [32] (Shukunami 2018) [33] | Scleraxis knockdown in equine embryonic stem cells, and fetal and adult tendon cells | Decreased expression of Col I, COMP, and Sox9, and reduced cell survival in embryonic stem cells and fetal tendon cells with scleraxis knockdown; adult tendon cells unaffected | Bavin 2017 [45] |
Scleraxis knockout in mice, and scleraxis knockdown in isolated rat tendon cells | Decreased or absent tenomodulin expression at P1 in scleraxis −/− mice; tenomodulin expression reduced to 17% of control by scleraxis knockdown in rat tendon cells | Shukunami 2018 [46] | |
Mohawk knockout in rats via CRISPR/Cas9 | Heterotropic mineralization of Achilles tendons and tendon hypoplasia in 3 and 4-week-old rats; increased expression of Col II, Runx2, Aggrecan, COMP, and osteopontin in patellar tendon cells | Suzuki 2016 [47] | |
Overexpression of mohawk and scleraxis in mouse MSCs and cell sheets | Increased expression of Col I, biglycan, Col III, Col V, Col XIV, decorin, fibromodulin, tenascin C, tenomodulin, and scleraxis via binding to the TGFβ2 promoter | Liu 2015 [31] | |
Overexpression of mohawk in human and mouse bone marrow-derived MSCs | Increased expression of Col I, tenomodulin, tenascin C, tenascin XB, scleraxis | Otabe 2015 [32] | |
Overexpression of scleraxis in human MSCs in a silk-collagen scaffold | Increased expression of tenogenic genes, cell alignment, and fibril diameter | Chen 2014 [48] | |
FGF4 (Edom-Vovard 2002) [49] (Brent 2005) [50] (Havis 2014) [42] | Mouse MSCs and chick limb explants | Species-specific scleraxis expression: decreased in mouse or increased in chick | Havis 2014 [42] Havis 2016 [43] |
Mouse embryonic tendon progenitor cells and MSCs | No changes or decreased scleraxis expression | Brown 2014 [40] Brown 2015 [41] | |
BMPs (Lorda-Diez 2014) [38] (Liu 2015) [31] (Otabe 2015) [32] | Chick progenitor mesodermal cells | Transient gene expression determines response to BMP isoforms | Lorda Diez 2014 [54] |
Human bone marrow-derived MSCs | BMP-12 increased mohawk, scleraxis, Col I, tenascin XB, and decorin expression | Otabe 2015 [32] | |
LOX and Mechanical Stimuli (Marturano 2013) [51] (Pan 2018) [52] | Embryonic chick tendon and limb explants | Paralysis decreased elastic modulus and LOX, hypermotility increased LOX and elastic modulus, LOX inhibition decreased elastic modulus | Pan 2018 [55] |
Lengthening/slow stretching (Hamburger & Hamilton 1951) [53] | Embryonic chick tendon cells in fibrin gels stretched 2 mm/day | Increased collagen fibril diameter, packing volume, and stiffness | Kalson 2011 [56] |
Elastic modulus (Marturano 2013) [51] | RGD-functionalized alginate gels with embryonic-mimicking elastic modulus | Scleraxis, Col XII, and Col I gene expression regulated by elastic modulus | Marturano 2016 [57] |
Progressive mineralization of tendon to bone attachment (Thomopoulos 2010) [12] | FEA model of cell- and tissue-level stress concentrations | Cell-level stresses much higher than tissue-level stresses; higher stresses may drive enthesis formation | Liu 2014 [58] |