Origin of tendon stem cells in situ

Abstract

BACKGROUND: Adult stem cells are surveillance repositories capable of supplying a renewable source of progenitors for tissue repair and regeneration to maintain tissue homeostasis throughout life. Many tissue-resident stem cells have been identified in situ, which lays the foundation for studying them in their native microenvironment, i.e. the niche. Within the musculoskeletal system, muscle stem cells have been unequivocally identified in the mouse, which have led to considerable advances in understanding their role in muscle homeostasis and regeneration. On the other hand, for bone and tendon progenitor cells, mesenchymal stem cells have been used as the main in vitro cell model as they can differentiate into osteogenic, chondrogenic and tenogenic fates. Despite considerable efforts and employment of modern tools, the in vivo origins of bone and tendon stem cells remain debated. Tendon regeneration via stem cells is understudied and deserves attention as tendon damage is noted for a bleak, time-consuming recovery and the repaired tendon seldom regains the structural integrity and strength of the native, uninjured state.

OBJECTIVE: Here we review the past efforts and recent studies toward defining adult tendon stem cells and understanding tendon regeneration instead of tendon development. The focus is on adult tendon resident cells in situ and the uncertainty of their roles in regeneration.

METHODS: A systematic literature search using the Pubmed search engine was conducted encompassing the seminal papers in the tendon field.

CONCLUSIONS: Investigation of tendon stem cells in situ is in its infancy mainly due to lack of necessary tools and standardized injury model. We propose a concerted effort toward establishing a comprehensive cell atlas of the tendon, making genetic tools and choosing a reliable injury model for coordinated studies among different laboratories. Increasing our basic understanding should aid future therapeutic innovations to shorten and enhance the tendon repair/regeneration process.

Keywords

Tendon / stem cells / midsubstance / sheath / injury

References

[1] Agarwal S, Loder S J, Cholok D, Peterson J, Li J, Breuler C, Cameron Brownley R, Hsin Sung H, Chung M T, Kamiya N, Li S, Zhao B, Kaartinen V, Davis T A, Qureshi A T, Schipani E, Mishina Y, Levi B (2017). Scleraxis-lineage cells contribute to ectopic bone formation in muscle and tendon. Stem Cells, 35(3): 705–710

[2] Anderson D M, Arredondo J, Hahn K, Valente G, Martin J F, Wilson-Rawls J, Rawls A (2006). Mohawk is a novel homeobox gene expressed in the developing mouse embryo. Dev Dyn, 235(3): 792–801

[3] Arble J R, Lalley A L, Dyment N A, Joshi P, Shin D G, Gooch C, Grawe B, Rowe D, Shearn J T (2016). The LG/J murine strain exhibits near-normal tendon biomechanical properties following a full-length central patellar tendon defect. Connect Tissue Res, 57(6): 496–506

[4] Ateschrang A, Ahmad S S, Stöckle U, Schroeter S, Schenk S, Ahrend M D (2017). Recovery of ACL function after dynamic intraligamentary stabilization is resultant to restoration of ACL integrity and scar tissue formation. Knee Surg Sports Tramatol Arthrosc

[5] Bagchi R A and Czubryt M P (2012). Synergistic roles of scleraxis and Smads in the regulation of collagen 1a2 gene expression. Biochim Biophys Acta, 1823(10): 1936–1944

[6] Bajpai V K, Mistriotis P, Andreadis S T (2012). Clonal multipotency and effect of long-term in vitro expansion on differentiation potential of human hair follicle derived mesenchymal stem cells. Stem Cell Res (Amst), 8(1): 74–84

[7] Baksh N, Hannon C P, Murawski C D, Smyth N A, Kennedy J G (2013). Platelet-rich plasma in tendon models: a systematic review of basic science literature. Arthroscopy, 29(3): 596–607

[8] Bao Z Z, Lakonishok M, Kaufman S, Horwitz A F (1993). Alpha 7 beta 1 integrin is a component of the myotendinous junction on skeletal muscle. J Cell Sci, 106(Pt 2): 579–589

[9] Barker N, van Es J H, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters P J, Clevers H (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165): 1003–1007

[10] Beason D P, Kuntz A F, Hsu J E, Miller K S, Soslowsky L J (2012). Development and evaluation of multiple tendon injury models in the mouse. J Biomech, 45(8): 1550–1553

[11] Benjamin M and Ralphs J R (1998). Fibrocartilage in tendons and ligaments--an adaptation to compressive load. J Anat, 193(4): 481–494

[12] Berthet E, Chen C, Butcher K, Schneider R A, Alliston T, Amirtharajah M (2013). Smad3 binds Scleraxis and Mohawk and regulates tendon matrix organization. J Orthop Res, 31(9): 1475–1483

[13] Bi Y, Ehirchiou D, Kilts T M, Inkson C A, Embree M C, Sonoyama W, Li L, Leet A I, Seo B M, Zhang L, Shi S, Young M F (2007). Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med, 13(10): 1219–1227

[14] Brent A E, Schweitzer R, Tabin C J (2003). A somitic compartment of tendon progenitors. Cell, 113(2): 235–248

[15] Brent A E, Tabin C J (2004). FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression. Development, 131(16): 3885–3896

[16] Buschmann J, Bürgisser G M ( 2017). Biomechanics on tendons and ligaments. Zurich: Elsevier, Print

[17] Cairns J (1975). Mutation selection and the natural history of cancer. Nature, 255(5505): 197–200

[18] Calve S, Dennis R G, Kosnik P E 2nd, Baar K, Grosh K, Arruda E M (2004). Engineering of functional tendon. Tissue Eng, 10(5-6): 755–761

[19] Chan B P, Fu S, Qin L, Lee K, Rolf C G, Chan K (2000). Effects of basic fibroblast growth factor (bFGF) on early stages of tendon healing: a rat patellar tendon model. Acta Orthop Scand, 71(5): 513–518

[20] Chang J, Thunder R, Most D, Longaker M T, Lineaweaver W C (2000). Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast Reconstr Surg, 105(1): 148–155

[21] Charvet B, Ruggiero F, Le Guellec D (2012). The development of the myotendinous junction. A review. Muscles Ligaments Tendons J, 2(2): 53–63

[22] Chien C, Pryce B, Tufa S F, Keene D R, Huang A H (2017). Optimizing a 3D model system for molecular manipulation of tenogenesis. Connect Tissue Res, 22: 1–14

[23] Covas D T, Panepucci R A, Fontes A M, Silva W A Jr, Orellana M D, Freitas M C, Neder L, Santos A R, Peres L C, Jamur M C, Zago M A (2008). Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol, 36(5): 642–654

[24] Cserjesi P, Brown D, Ligon K L, Lyons G E, Copeland N G, Gilbert D J, Jenkins N A, Olson E N (1995). Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis. Development, 121(4): 1099–1110

[25] Dahlgren L A, van der Meulen M C, Bertram J E, Starrak G S, Nixon A J (2002). Insulin-like growth factor-I improves cellular and molecular aspects of healing in a collagenase-induced model of flexor tendinitis. J Orthop Res, 20(5): 910–919

[26] Dorrell C, Erker L, Schug J, Kopp J L, Canaday P S, Fox A J, Smirnova O, Duncan A W, Finegold M J, Sander M, Kaestner K H, Grompe M (2011). Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev, 25(11): 1193–1203

[27] Dyment N A, Breidenbach A P, Schwartz A G, Russell R P, Aschbacher-Smith L, Liu H, Hagiwara Y, Jiang R, Thomopoulos S, Butler D L, Rowe D W (2015). Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev Biol, 405(1): 96–107

[28] Dyment N A, Hagiwara Y, Matthews B G, Li Y, Kalajzic I, Rowe D W (2014). Lineage tracing of resident tendon progenitor cells during growth and natural healing. PLoS One, 9(4): e96113

[29] Edom-Vovard F, Duprez D (2004). Signals regulating tendon formation during chick embryonic development. Dev Dyn, 229(3): 449–457

[30] Elliott D H (1965). Structure and Function of Mammalian Tendon. Biol Rev Camb Philos Soc, 40(3): 392–421

[31] Feil R, Wagner J, Metzger D, Chambon P (1997). Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun, 237(3): 752–757

[32] Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P (1996). Ligand-activated site-specific recombination in mice. PNAS 93: 10887–10890

[33] Franchi M, Trirè A, Quaranta M, Orsini E, Ottani V (2007). Collagen structure of tendon relates to function. Sci World J, 7: 404–420

[34] Frolova E G, Drazba J, Krukovets I, Kostenko V, Blech L, Harry C, Vasanji A, Drumm C, Sul P, Jenniskens G J, Plow E F, Stenina-Adognravi O (2014). Control of organization and function of muscle and tendon by thrombospondin-4. Matrix Biol, 37: 35–48

[35] Fukui N, Katsuragawa Y, Sakai H, Oda H, Nakamura K (1998). Effect of local application of basic fibroblast growth factor on ligament healing in rabbits. Rev Rhum Engl Ed, 65(6): 406–414

[36] Gaut L, Duprez D (2016). Tendon development and diseases. Dev Biol, 5(1): 5–23

[37] Gaut L, Robert N, Delalande A, Bonnin M A, Pichon C, Duprez D (2016). EGR1 regulates transcription downstream of mechanical signals during tendon formation and healing. PLoS One, 11(11): e0166237

[38] Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina M E, Ordóñez-Morán P, Clevers H, Lutolf M P (2016). Designer matrices for intestinal stem cell and organoid culture. Nature, 539(7630): 560–564

[39] Grcevic D, Pejda S, Matthews B G, Repic D, Wang L, Li H, Kronenberg M S, Jiang X, Maye P, Adams D J, Rowe D W, Aguila H L, Kalajzic I (2012). In vivo fate mapping identifies mesenchymal progenitor cells. Stem Cells, 30(2): 187–196

[40] Guerquin M J, Charvet B, Nourissat G, Havis E, Ronsin O, Bonnin M A, Ruggiu M, Olivera-Martinez I, Robert N, Lu Y, Kadler K E, Baumberger T, Doursounian L, Berenbaum F, Duprez D (2013). Transcription factor EGR1 directs tendon differentiation and promotes tendon repair. J Clin Invest, 123(8): 3564–3576

[41] Gumucio J P, Phan A C, Ruehlmann D G, Noah A C, Mendias C L (2014). Synergist ablation induces rapid tendon growth through the synthesis of a neotendon matrix. J Appl Physiol (1985), 117(11): 1287–1291

[42] Hall T E, Bryson-Richardson R J, Berger S, Jacoby A S, Cole N J, Hollway G E, Berger J, Currie P D (2007). The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin 2-deficient congenital muscular dystrophy. Proc Natl Acad Sci USA, 104(17): 7092–7

[43] Hexter A T, Pendegrass C, Haddad F, Blunn G (2017). Demineralized Bone Matrix to Augment Tendon-Bone Healing: A Systematic Review. Orthop J Sports Med, 5(10): 2325967117734517

[44] Hildebrand K A, Woo S L, Smith D W, Allen C R, Deie M, Taylor B J, Schmidt C C (1998). The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. An in vivo study. Am J Sports Med, 26(4): 549–554

[45] Hoffman P N, Cleveland D W (1988). Neurofilament and tubulin expression recapitulates the developmental program during axonal regeneration: induction of a specific b-tubulin isotype. Proc Natl Acad Sci USA, 85(12): 4530–4533

[46] Howell K, Chien C, Bell R, Laudier D, Tufa S F, Keene D R, Andarawis-Puri N, Huang A H (2017) Novel model of tendon regeneration reveals distinct cell mechanisms underlying regenerative and fibrotic tendon healing. Sci Rep, 7: 45238

[47] Huang A H, Lu H H, Schweitzer R (2015). Molecular regulation of tendon cell fate during development. J Orthop Res, 33(6): 800–812

[48] Ibraghimov-Beskrovnaya O, Ervasti J M, Leveille C J, Slaughter C A, Sernett S W, Campbell K P (1992). Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature, 355(6362): 696–702

[49] Imokawa Y, Yoshizato K (1997). Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. Proc Natl Acad Sci USA, 94(17): 9159–9164

[50] Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S, Nishida K, Akimoto T, Takahashi M, Miyaki S, Asahara H (2010). The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci USA, 107(23): 10538–10542

[51] Ivkovic S, Yoon B S, Popoff S N, Safadi F F, Libuda D E, Stephenson R C, Daluiski A, Lyons K M (2003). Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development, 130(12): 2779–2791

[52] Kajikawa Y, Morihara T, Sakamoto H, Matsuda K, Oshima Y, Yoshida A, Nagae M, Arai Y, Kawata M, Kubo T (2008). Platelet-rich plasma enhances the initial mobilization of circulation-derived cells for tendon healing. J Cell Physiol, 215(3): 837–845

[53] Kaux J F, Janssen L, Drion P, Nusgens B, Libertiaux V, Pascon F, Heyeres A, Hoffmann A, Lambert C, Le Goff C, Denoël V, Defraigne J O, Rickert M, Crielaard J M, Colige A (2014). Vascular Endothelial Growth Factor-111 (VEGF-111) and tendon healing: preliminary results in a rat model of tendon injury. Muscles Ligaments Tendons J, 4(1): 24–28

[54] Kirkendall D T and Garrett W E (1997). Function and biomechanics of tendons. Scand J Med Sci Sports, 7(2): 62–66

[55] Kretzschmar K and Watt F M (2012). Lineage tracing. Cell, 148(1-2): 33–45

[56] Kurth T B, Dell’Accio F, Crouch V, Augello A, Sharpe P T, De Bari C (2011). Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum, 63(5): 1289–1300

[57] Kurtz C A, Loebig T G, Anderson D D, DeMeo P J, Campbell P G (1999). Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med, 27(3): 363–369

[58] Lalley A L, Dyment N A, Kazemi N, Kenter K, Gooch C, Rowe D W, Butler D L, Shearn J T (2015). Improved biomechanical and biological outcomes in the MRL/MpJ murine strain following a full-length patellar tendon injury. J Orthop Res, 33(11): 1693–1703

[59] Lee C H, Lee F Y, Tarafder S, Kao K, Jun Y, Yang G, Mao J J (2015). Harnessing endogenous stem/progenitor cells for tendon regeneration. J Clin Invest, 125(7): 2690–2701

[60] Léjard V, Blais F, Guerquin M J, Bonnet A, Bonnin M A, Havis E, Malbouyres M, Bidaud C B, Maro G, Gilardi-Hebenstreit P, Rossert J, Ruggiero F, Duprez D (2011). EGR1 and EGR2 involvement in vertebrate tendon differentiation. J Biol Chem, 286(7): 5855–5867

[61] Léjard V, Brideau G, Blais F, Salingcarnboriboon R, Wagner G, Roehrl M H, Noda M, Duprez D, Houillier P, Rossert J (2007). Scleraxis and NFATc regulate the expression of the pro-a1(I) collagen gene in tendon fibroblasts. J Biol Chem, 282(24): 17665–17675

[62] Leong D J, Sun H B (2016). Mesenchymal stem cells in tendon repair and regeneration: basic understanding and translational challenges. Ann N Y Acad Sci, 1383(1): 88–96

[63] Letson A K, Dahners L E (1994). The effect of combinations of growth factors on ligament healing. Clin Orthop Relat Res, (308): 207–212

[64] Levay A K, Peacock J D, Lu Y, Koch M, Hinton R B Jr, Kadler K E, Lincoln J (2008). Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo. Circ Res, 103(9): 948–956

[65] Li L and Clevers H (2010). Coexistence of quiescent and active adult stem cells in mammals. Science, 327(5965): 542–545

[66] Lin T W, Cardenas L, Glaser D L, Soslowsky L J (2006). Tendon healing in interleukin-4 and interleukin-6 knockout mice. J Biomech, 39(1): 61–69

[67] Liu C F, Aschbacher-Smith L, Barthelery N J, Dyment N, Butler D, and Wylie C (2012). Spatial and temporal expression of molecular markers and cell signals during normal development of the mouse patellar tendon. Tissue Eng Part A, 18(5-6): 598–608

[68] Liu H, Xu J, Liu C F, Lan Y, Wylie C, Jiang R (2015). Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J Orthop Res, 33(6): 840–848

[69] Liu R, Zhang Z, Xu Y (2010). Downregulation of nucleostemin causes G1 cell cycle arrest via a p53-independent pathway in prostate cancer PC-3 cells. Urol Int, 85(2): 221–227

[70] Liu Z, Martin L J (2003). Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human. J Comp Neurol, 459(4): 368–391

[71] Lu H H, Thomopoulos S (2013). Functional attachment of soft tissues to bone: development, healing, and tissue engineering. Annu Rev Biomed Eng, 15(1): 201–226

[72] Lui P, Zhang P, Chan K, Qin L (2010). Biology and augmentation of tendon-bone insertion repair. J Orthop Surg, 5(1): 59

[73] Lyras D N, Kazakos K, Verettas D, Botaitis S, Agrogiannis G, Kokka A, Pitiakoudis M, Kotzakaris A (2009). The effect of platelet-rich plasma gel in the early phase of patellar tendon healing. Arch Orthop Trauma Surg, 129(11): 1577–1582

[74] Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera A L, Keene D R, Sasaki T, Stavnezer E, Iannotti J, Schweitzer R, Ilic D, Baskaran H, Sakai T (2011). Conversion of mechanical force into TGF-b-mediated biochemical signals. Curr Biol, 21(11): 933–941

[75] Mendias C L, Gumucio J P, Bakhurin K I, Lynch E B, Brooks S V (2012). Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts. J Orthop Res, 30(4): 606–612

[76] Miosge N, Klenczar C, Herken R, Willem M, Mayer U (1999). Organization of the myotendinous junction is dependent on the presence of alpha7beta1 integrin. Lab Invest, 79(12): 1591–1599

[77] Molloy T, Wang Y, Murrell G (2003). The roles of growth factors in tendon and ligament healing. Sports Med, 33(5): 381–394

[78] Murchison N D, Price B A, Conner D A, Keene D R, Olson E N, Tabin C J, Schweitzer R (2007). Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development, 134: 2697–2708

[79] Paxton J Z, Donnelly K, Keatch R P, Baar K (2009). Engineering the bone-ligament interface using polyethylene glycol diacrylate incorporated with hydroxyapatite. Tissue Eng Part A, 15(6): 1201–1209

[80] Paxton J Z, Grover L M, Baar K (2010). Engineering an in vitro model of a functional ligament from bone to bone. Tissue Eng Part A, 16(11): 3515–3525

[81] Perez A V, Perrine M, Brainard N, Vogel K G (2003). Scleraxis (Scx) directs lacZ expression in tendon of transgenic mice. Mech Dev, 120(10): 1153–1163

[82] Petersen J R, Agarwal S, Brownley R C, Loder S J, Ranganathan K, Cederna P S, Mishina Y, Wang S C, Levi B (2015). Direct mouse trauma/burn model for heterotopic ossification. J Vis Exp (102): 52880

[83] Petersen W, Fink C, Kopf S (2017). Return to sports after ACL reconstruction: a paradigm shift from time to function. Knee Surg Sports Traumatol Arthrosc, 25(5): 1353–1355

[84] Potten C S, Hendry J H (1975). Differential regeneration of intestinal proliferative cells and cryptogenic cells after irradiation. Int J Radiat Biol Relat Stud Phys Chem Med, 27(5): 413–424

[85] Pryce B A, Brent A E, Murchison N D, Tabin C J, Schweitzer R (2007). Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn, 236(6): 1677–1682

[86] Pryce B A, Watson S S, Murchison N D, Staverosky J A, Dünker N, Schweitzer R (2009). Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development, 136(8): 1351–1361

[87] Rees S G, Waggett A D, Kerr B C, Probert J, Gealy E C, Dent C M, Caterson B, Hughes C E (2009). Immunolocalisation and expression of keratocan in tendon. Osteoarthritis Cartilage, 17(2): 276–279

[88] Richardson S H, Starborg T, Lu Y, Humphries S M, Meadows R S, Kadler K E (2007). Tendon development requires regulation of cell condensation and cell shape via cadherin-11-mediated cell-cell junctions. Mol Cell Biol, 27(17): 6218–6228

[89] Rickert M, Jung M, Adiyaman M, Richter W, and Simank H G (2001). A growth and differentiation factor-5 (GDF-5)-coated suture stimulates tendon healing in an Achilles tendon model in rats. Growth Factors, 19(2): 115–126

[90] Rountree R B, Schoor M, Chen H, Marks M E, Harley V, Mishina Y, Kingsley D M (2004). BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol, 2(11): e355

[91] Rubio-Azpeitia E, Sánchez P, Delgado D, Andia I (2015). Three-dimensional platelet rich plasma hydrogel model to study early tendon healing. Cells Tissues Organs, 200(6): 394–404

[92] Runesson E, Ackermann P, Brisby H, Karlsson J, Eriksson B I (2013). Detection of slow-cycling and stem/progenitor cells in different regions of rat Achilles tendon: response to treadmill exercise. Knee Surg Sports Traumatol Arthrosc, 21(7): 1694–1703

[93] Runesson E, Ackermann P, Karlsson J, Eriksson B I (2015). Nucleostemin- and Oct 3/4-positive stem/progenitor cells exhibit disparate anatomical and temporal expression during rat Achilles tendon healing. BMC Musculoskelet Disord, 16(212): 1

[94] Sato T, Vries R G, Snippert H J, van de Wetering M, Barker N, Stange D E, van Es J H, Abo A, Kujala P, Peters P J, Clevers H (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459(7244): 262–265

[95] Schwartz A G, Galatz L M, Thomopoulos S (2017). Enthesis regeneration: a role for Gli1+ progenitor cells. Development, 144(7): 1159–1164

[96] Schwartz Y, Viukov S, Krief S, Zelzer E (2016). Joint development involves a continuous influx of Gdf5-positive cells. Cell Reports, 15(12): 2577–2587

[97] Schweitzer R, Chyung J H, Murtaugh L C, Brent A E, Rosen V, Olson E N, Lassar A, Tabin C J (2001). Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development, 128(19): 3855–3866

[98] Shah R R, Nerurkar N L, Wang C C, Galloway J L (2015). Tensile properties of craniofacial tendons in the mature and aged zebrafish. J Orthop Res, 33(6): 867–873

[99] Shih I M (1999). The role of CD146 (Mel-CAM) in biology and pathology. J Pathol, 189(1): 4–11

[100] Shukunami C, Takimoto A, Oro M, Hiraki Y (2006). Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol, 298(1): 234–247

[101] Snippert H J, van der Flier L G, Sato T, van Es J H, van den Born M, Kroon-Veenboer C, Barker N, Klein A M, van Rheenen J, Simons B D, Clevers H (2010). Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell, 143(1): 134–144

[102] Soriano P (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet, 21(1): 70–71

[103] Starborg T, Kalson N S, Lu Y, Mironov A, Cootes T F, Holmes D F, Kadler K E (2013). Using transmission electron microscopy and 3View to determine collagen fibril size and three-dimensional organization. Nat Protoc, 8(7): 1433–1448

[104] Staverosky J A, Pryce B A, Watson S S, Schweitzer R (2009). Tubulin polymerization-promoting protein family member 3, Tppp3, is a specific marker of the differentiating tendon sheath and synovial joints. Dev Dyn, 238(3): 685–692

[105] Subramanian A and Schilling T F (2014). Thrombospondin-4 controls matrix assembly during development and repair of myotendinous junctions. eLife, 3: e02372

[106] Subramanian A and Schilling T F (2015). Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix. Development, 142(24): 4191–4204

[107] Subramanian A, Wayburn B, Bunch T, Volk T (2007). Thrombospondin-mediated adhesion is essential for the formation of the myotendinous junction in Drosophila. Development, 134(7): 1269–1278

[108] Sugimoto Y, Takimoto A, Hiraki Y, Shukunami C (2013). Generation and characterization of ScxCre transgenic mice. Genesis, 51(4): 275–283

[109] Sundar S, Pendegrass C J, Blunn G W (2009). Tendon bone healing can be enhanced by demineralized bone matrix: a functional and histological study. J Biomed Mater Res B Appl Biomater, 88B(1): 115–122

[110] Tan Q, Lui P P Y, Lee Y W (2013). In vivo identity of tendon stem cells and the roles of stem cells in tendon healing. Stem Cells Dev, 22(23): 3128–3140

[111] Thomopoulos S, Williams G R, Gimbel J A, Favata M, Soslowsky L J (2003). Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res, 21(3): 413–419

[112] Tidball J G, Lin C (1989). Structural changes at the myogenic cell surface during the formation of myotendinous junctions. Cell Tissue Res, 257(1): 77–84

[113] Urdzikova L M, Sedlacek R, Suchy T, Amemori T, Ruzicka J, Lesny P, Havlas V, Sykova E, Jendelova P (2014). Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat. Biomed Eng Online, 13(42): 1–15

[114] Veronesi F, Salamanna F, Tschon M, Maglio M, Nicoli Aldini N, Fini M (2017). Mesenchymal stem cells for tendon healing: what is on the horizon? J Tissue Eng Regen Med, 11(11): 3202–3219

[115] Wang Y, Zhang X, Huang H, Xia Y, Yao Y, Mak A F, Yung P S, Chan K M, Wang L, Zhang C, Huang Y, Mak K K (2017). Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling. eLife, 6: e30474

[116] Watson S S, Riordan T J, Pryce B A, Schweitzer R (2009). Tendons and muscles of the mouse forelimb during embryonic development. Dev Dyn, 238(3): 693–700

[117] Wolfman N M, Hattersley G, Cox K, Celeste A J, Nelson R, Yamaji N, Dube J L, DiBlasio-Smith E, Nove J, Song J J, Wozney J M, Rosen V (1997). Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family. J Clin Invest, 100(2): 321–330

[118] Wu Y, Wang Z, Ying Hsi Fuh J, San Wong Y, Wang W, San Thian E (2017). Direct E-jet printing of three-dimensional fibrous scaffold for tendon tissue engineering. J Biomed Mater Res B Appl Biomater, 105(3): 616–627

[119] Wu Y, Wong Y S, Fuh J Y H (2017). Degradation behaviors of geometric cues and mechanical properties in a 3D scaffold for tendon repair. J Biomed Mater Res A, 105(4): 1138–1149

[120] Yin H, Yan Z, Bauer R J, Peng J, Schieker M, Nerlich M, Docheva D (2018). Functionalized thermosensitive hydrogel combined with tendon stem/progenitor cells as injectable cell delivery carrier for tendon tissue engineering. Biomed Mater, 13(3): 034107

[121] Yoshimoto Y, Takimoto A, Watanabe H, Hiraki Y, Kondoh G, Shukunami C (2017). Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system. Sci Rep, 7: 1-16

[122] Zampeli F, Terzidis I, Espregueiera-Mendes J, Georgoulis J D, Bernard M, Pappas E, Georgoulis A D (2017). Restoring tibiofemoral alignment during ACL reconstruction results in better knee biomechanics. Knee Surg Sports Traumatol Arthrosc, 25(6): 1367-1374

[123] Zhang J and Wang J H C (2010). Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet Disord, 11(10): 1

[124] Zhang Y, Kao W W Y, Hayashi Y, Zhang L, Call M, Dong F, Yuan Y, Zhang J, Wang Y C, Yuka O, Shiraishi A, Liu C Y (2017). Generation and characterization of a novel mouse line, Keratocan-rtTA (KeraRT), for corneal stroma and tendon research. Invest Ophthalmol Vis Sci, 58(11): 4800–4808

[125] Zheng G X Y, Terry J M, Belgrader P, Ryvkin P, Bent Z W, Wilson R, Ziraldo S B, Wheeler T D, McDermott G P, Zhu J, Gregory M T, Shuga J, Montesclaros L, Underwood J G, Masquelier D A, Nishimura S Y, Schnall-Levin M, Wyatt P W, Hindson C M, Bharadwaj R, Wong A, Ness K D, Beppu L W, Deeg H J, McFarland C, Loeb K R, Valente W J, Ericson N G, Stevens E A, Radich J P, Mikkelsen T S, Hindson B J, Bielas J H (2017). Massively parallel digital transcriptional profiling of single cells. Nat Commun, 8: 1-12

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