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Tendons transmit the muscle contraction forces to bones and drive joint movement throughout life. While extensive research have indicated the essentiality of mechanical forces on tendon development, a comprehensive understanding of the fundamental role of mechanical forces still needs to be impaerted. This scoping review aimed to summarize the current knowledge about the role of mechanical forces during the tendon developmental phase. The electronic database search using PubMed, performed in May 2023, yielded 651 articles, of which 16 met the prespecified inclusion criteria. We summarized and divided the methods to reduce the mechanical force into three groups: loss of muscle, muscle dysfunction, and weight‐bearing regulation. In contrast, there were few studies to analyze the increased mechanical force model. Most studies suggested that mechanical force has some roles in tendon development in the embryo to postnatal phase. However, we identified species variability and methodological heterogeneity to modulate mechanical force. To establish a comprehensive understanding, methodological commonality to modulate the mechanical force is needed in this field. Additionally, summarizing chronological changes in developmental processes across animal species helps to understand the essence of developmental tendon mechanobiology. We expect that the findings summarized in the current review serve as a groundwork for future study in the fields of tendon developmantal biology and mechanobiology. Key Findings: Recent mechano‐biological studies about tendon development have no consensus on the definition of mechanical force on the tendon. A clear definition of mechanical force based on species is needed to establish a comprehensive understanding of the role of mechanical force on tendon development. [ABSTRACT FROM AUTHOR]

The tendon field has been flourishing in recent years with the advent of new tools and model systems. The recent ORS 2022 Tendon Section Conference brought together researchers from diverse disciplines and backgrounds, showcasing studies in biomechanics and tissue engineering to cell and developmental biology and using models from zebrafish and mouse to humans. This perspective aims to summarize progress in tendon research as it pertains to understanding and studying tendon cell fate. The successful integration of new technologies and approaches have the potential to further propel tendon research into a new renaissance of discovery. However, there are also limitations with the current methodologies that are important to consider when tackling research questions. Altogether, we will highlight recent advances and technologies and propose new avenues to explore tendon biology. [ABSTRACT FROM AUTHOR]

The molecular cascade underlying tendon formation starts when progenitor cells begin to express the Scleraxis (Scx) gene. Scx knockout mice develop some but not all tendons, suggesting that additional factors are necessary for tendon commitment, maintenance, and differentiation. Other transcription factors, such as Mohawk (Mkx) or early growth response (Egr), maintain Scx expression and extracellular matrix formation during fibrillogenesis. The inhibition of wingless and int-related protein signaling is necessary and sufficient to induce the expression of Scx. Once the commitment of tenogenic lineage occurs, transforming growth factor-beta (TGFβ) induces the Scx gene expression, becoming involved in the maintenance of tendon cell fate. From this point of view, we discussed two phases of the tenogenic process during limb development: dependent and independent of mechanical forces. Finally, we highlight the importance of understanding embryonic tendon development to improve therapeutic strategies in regenerative medicines for tendons. [ABSTRACT FROM AUTHOR]

There is high clinical demand for the resolution of tendinopathies, which affect mainly adult individuals and animals. Tendon damage resolution during the adult lifetime is not as effective as in earlier stages where complete restoration of tendon structure and property occurs. However, the molecular mechanisms underlying tendon regeneration remain unknown, limiting the development of targeted therapies. The research aim was to draw a comparative map of molecules that control tenogenesis and to exploit systems biology to model their signaling cascades and physiological paths. Using current literature data on molecular interactions in early tendon development, species-specific data collections were created. Then, computational analysis was used to construct Tendon NETworks in which information flow and molecular links were traced, prioritized, and enriched. Species-specific Tendon NETworks generated a data-driven computational framework based on three operative levels and a stage-dependent set of molecules and interactions (embryo–fetal or prepubertal) responsible, respectively, for signaling differentiation and morphogenesis, shaping tendon transcriptional program and downstream modeling of its fibrillogenesis toward a mature tissue. The computational network enrichment unveiled a more complex hierarchical organization of molecule interactions assigning a central role to neuro and endocrine axes which are novel and only partially explored systems for tenogenesis. Overall, this study emphasizes the value of system biology in linking the currently available disjointed molecular data, by establishing the direction and priority of signaling flows. Simultaneously, computational enrichment was critical in revealing new nodes and pathways to watch out for in promoting biomedical advances in tendon healing and developing targeted therapeutic strategies to improve current clinical interventions.

Craniofacial (CF) tendons are often affected by traumatic injuries and painful disorders that can severely compromise critical jaw functions, such as mastication and talking. Unfortunately, tendons lack the ability to regenerate, and there are no solutions to restore their native properties or function. An understanding of jaw tendon development could inform tendon regeneration strategies to restore jaw function, however CF tendon development has been relatively unexplored. Using the chick embryo, we identified the jaw-closing Tendon of the musculus Adductor Mandibulae Externus (TmAM) and the jaw-opening Tendon of the musculus Depressor Mandibulae (TmDM) that have similar functions to the masticatory tendons in humans. Using histological and immunohistochemical (IHC) analyses, we characterized the TmAM and TmDM on the basis of cell and extracellular matrix (ECM) morphology and spatiotemporal protein distribution from early to late embryonic development. The TmAM and TmDM were detectable as early as embryonic day (d) 9 based on histological staining and tenascin-C (TNC) protein distribution. Collagen content increased and became more organized, cell density decreased, and cell nuclei elongated over time during development in both the TmAM and TmDM. The TmAM and TmDM exhibited similar spatiotemporal patterns for collagen type III (COL3), but differential spatiotemporal patterns for TNC, lysyl oxidase (LOX), and matrix metalloproteinases (MMPs). Our results demonstrate markers that play a role in limb tendon formation are also present in jaw tendons during embryonic development, implicate COL3, TNC, LOX, MMP2, and MMP9 in jaw tendon development, and suggest TmAM and TmDM possess different developmental programs. Taken together, our study suggests the chick embryo may be used as a model with which to study CF tendon extracellular matrix development, the results of which could ultimately inform therapeutic approaches for CF tendon injuries and disorders.

Tendon development requires the coordinated interaction of muscles and tendons. Muscle-derived cells (MDCs), a mixed cell population containing both myogenic and fibroblastic cell subsets, have been found to be ideal seed cells for tendon regeneration. However, the necessity of these cell types for tendon regeneration has not yet been tested. In this study, we aim to explore the possible synergistic effects of myogenic cells and fibroblasts in engineered tendon regeneration. MDCs were separated into rapidly adhering cell (RAC; fibroblasts) and slowly adhering cell (SAC; myogenic cells) populations. Myogenic- and tenogenic-related molecules were analyzed by immunofluorescent staining, RT-PCR and real-time PCR. The proliferative abilities of MDCs, RACs and SACs were also evaluated. Cell-scaffold constructs were implanted into nude mice, and subsequently evaluated for their histologic, ultrastructure, gene expression, and biomechanical characteristics. MDCs have better proliferative activity than RAC and SAC population. RACs could express higher levels of tenogenic-related molecules tenomodulin (TNMD) and scleraxis (SCX) than SACs. Whereas SACs only expressed myogenic-related molecules MyoD. In contrast to the tendons engineered using RACs and SACs, the tendons engineered using MDCs exhibited a relatively more mature and well-organized tissue structure and ultrastructure as well as better mechanical properties. Fibroblasts in muscle may be the primary cell population involved in tendon regeneration and that myogenic cells are an important component of the niche and control the fibroblast activity during tendon regeneration. The synergistic effects between fibroblasts and myogenic cells significantly contribute to efficient and effective regeneration of engineered tendons. [ABSTRACT FROM AUTHOR]

Suitable scaffold structures and mechanical loading are essential for functional tendon engineering. However, the bipolar fibril structure of native tendon collagen is yet to be recaptured in engineered tendons. This study compared the development of Achilles tendons of postnatal rats with and without (via surgical section) mechanical loading to define the mechanism of mechanical stimulation-mediated tendon development. The results demonstrated that the severed tendons weakened mechanically and exhibited disorganization without a bipolar fibril superstructure. Proteomic analysis revealed differentially expressed key regulatory molecules related to the collagen assembly process, including decreased fibromodulin, keratocan, fibroblast growth factor-1, and increased lumican and collagen5a1 in the severed tendons with immunohistochemical verification. Additionally, a complex regulatory network of mechanical stimulation-mediated collagen assembly in a spatiotemporal manner was also revealed using bioinformatics analysis, wherein PI3K–Akt and HDAC4 may be the predominant signaling pathways. A wavy microgrooved surface (Y = 5.47sin(0.015x)) that biomimics tendon topography was observed to enhance the expression of collagen assembly molecules under mechanical loading, and the aforementioned pathways are particularly involved and verified with their respective inhibitors of LY-294002 and LMK-235. Furthermore, an electrospun crimped nanofiber scaffold (approximately 2 μm fiber diameter and 0.12 crimpness) was fabricated to biomimic the tenogenic niche environment; this was observed to be more effective on enhancing collagen production and assembly under mechanical stimulation. In conclusion, the synergistic effect between topographical niche and mechanical stimulation was observed to be essential for collagen assembly and maturation and should be applied to functional tendon engineering in the future. In biomaterial-mediated tendon regeneration, mechanical stimulation is essential for tendon collagen assembly. However, the underlying mechanisms remain not fully defined, leading to the failure of the native-like collagen regeneration. In this study, a mechanical stimulation deprivation model of rat tendon was established to reveal the mechanisms in tendon development and define the key regulatory molecules including small leucine-rich proteoglycans, lysyl oxidase and collagen V. After ensuring the importance of biomimetic structure in tendon remodeling, crimped nanofibers were developed to verify these regulatory molecules, and demonstrated that mechanical stimulation significantly enhanced collagen assembly via PIK3 and HDAC4 pathways in biomaterial-regulated tendon regeneration. This study provides more insightful perspectives in the physiologically remodeling progression of tendon collagen and design of tendon scaffolds. [Display omitted] [ABSTRACT FROM AUTHOR]

During embryonic development, tendons transform into a hypocellular tissue with robust tensile load-bearing capabilities. Previous work suggests that this mechanical transformation is due to increases in collagen fibril length and is dependent on mechanical stimulation via muscle activity. However, the relationship between changes in the microscale tissue structure and changes in macroscale tendon mechanics is still unclear. Additionally, the specific effect of mechanical stimulation on the multiscale structure-function relationships of developing tendons is also unknown. Therefore, the objective of this study was to measure the changes in tendon mechanics and structure at multiple length scales during embryonic development with and without skeletal muscle paralysis. Tensile testing of tendons from chick embryos was performed to determine the macroscale tensile modulus as well as the magnitude of the fibril strains and interfibrillar sliding with applied tissue strain. Embryos were also treated with either decamethonium bromide or pancuronium bromide to produce rigid or flaccid paralysis. Histology was performed to assess changes in tendon size, spacing between tendon subunits, and collagen fiber diameter. We found that the increase in the macroscale modulus observed with development is accompanied by an increase in the fibril:tissue strain ratio, which is consistent with an increase in collagen fibril length. Additionally, we found that flaccid paralysis reduced the macroscale tendon modulus and the fibril:tissue strain ratio, whereas less pronounced effects that were not statistically significant were observed with rigid paralysis. Finally, skeletal paralysis also reduced the size of collagen fibril bundles (i.e., fibers). Together, these data suggest that more of the applied tissue strain is transmitted to the collagen fibrils at later embryonic ages, which leads to an increase in the tendon macroscale tensile mechanics. Furthermore, our data suggest that mechanical stimulation during development is necessary to induce structural and mechanical changes at multiple physical length scales. This information provides valuable insight into the multiscale structure-function relationships of developing tendons and the importance of mechanical stimulation in producing a robust tensile load-bearing soft tissue.

Tendons are extracellular matrix (ECM)-rich structures that mediate muscle attachments with the skeleton, but surprisingly little is known about molecular mechanisms of attachment. Individual myofibers and tenocytes in Drosophila interact through integrin (Itg) ligands such as Thrombospondin (Tsp), while vertebrate muscles attach to complex ECM fibrils embedded with tenocytes. We show for the first time that a vertebrate thrombospondin, Tsp4b, is essential for muscle attachment and ECM assembly at myotendinous junctions (MTJs). Tsp4b depletion in zebrafish causes muscle detachment upon contraction due to defects in laminin localization and reduced Itg signaling at MTJs. Mutation of its oligomerization domain renders Tsp4b unable to rescue these defects, demonstrating that pentamerization is required for ECM assembly. Furthermore, injected human TSP4 localizes to zebrafish MTJs and rescues muscle detachment and ECM assembly in Tsp4b-deficient embryos. Thus Tsp4 functions as an ECM scaffold at MTJs, with potential therapeutic uses in tendon strengthening and repair.

The transcription factor scleraxis (Scx) is required for tendon development; however, the function of Scx is not fully understood. Although Scx is expressed by all tendon progenitors and cells, only long tendons are disrupted in the Scx-/- mutant; short tendons appear normal and the ability of muscle to attach to skeleton is not affected. We recently demonstrated that long tendons are formed in two stages: first, by muscle anchoring to skeleton via a short tendon anlage; and second, by rapid elongation of the tendon in parallel with skeletal growth. Through lineage tracing, we extend these observations to all long tendons and show that tendon elongation is fueled by recruitment of new mesenchymal progenitors. Conditional loss of Scx in mesenchymal progenitors did not affect the first stage of anchoring; however, new cells were not recruited during elongation and long tendon formation was impaired. Interestingly, for tenocyte recruitment, Scx expression was required only in the recruited cells and not in the recruiting tendon. The phenotype of Scx mutants can thus be understood as a failure of tendon cell recruitment during tendon elongation. [ABSTRACT FROM AUTHOR]

Patellar tendon pathology appears to develop in young athletes. It is not known how this tendon develops through adolescence. This longitudinal study investigated proximal patellar tendon development during the adolescent growth spurt in young ballet dancers and identified whether puberty (estimated by maturity offset) had an effect on tendon development. Fifty two dancers (32 female and 20 male dancers, ages 11‐18 at baseline) had ultrasound images of their tendons every 6 months for 2 years. Changes in tendon size (anterior‐posterior diameter) on grayscale images and echogenicity, as quantified using ultrasound tissue characterization, were recorded each time. Maturity offset was calculated used to estimate peak height velocity (adolescent growth spurt). Maturity offset did not affect effect tendon composition before peak height velocity; however, after participants passed peak height velocity, maturity offset increased the composition of stable echopattern (P < .05): a 4% differential increase in type I echopattern, indicative of normal tendon structure, and a decrease in type III echopattern (more disorganized echopattern) by 0.7% per year. Anterior‐posterior thickness increased by 0.2 mm/y (P < .05) measured 2 cm below the patella. Following peak height velocity, the proximal patellar tendon attachment increased in thickness and demonstrated a more stable echopattern representative of aligned fibrillar structure. Future research is required to further understand this normal maturation and the factors that support this process, with the aim of reducing the development of patellar tendon pathology in the adolescent jumping athlete. [ABSTRACT FROM AUTHOR]

Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx)-/- rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx-/- mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx-/- mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx-/- TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx+/+ TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9. Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering. [ABSTRACT FROM AUTHOR]

Tendons are extracellular matrix (ECM)-rich structures that mediate muscle attachments with the skeleton, but surprisingly little is known about molecular mechanisms of attachment. Individual myofibers and tenocytes in Drosophila interact through integrin (Itg) ligands such as Thrombospondin (Tsp), while vertebrate muscles attach to complex ECM fibrils embedded with tenocytes. We show for the first time that a vertebrate thrombospondin, Tsp4b, is essential for muscle attachment and ECM assembly at myotendinous junctions (MTJs). Tsp4b depletion in zebrafish causes muscle detachment upon contraction due to defects in laminin localization and reduced Itg signaling at MTJs. Mutation of its oligomerization domain renders Tsp4b unable to rescue these defects, demonstrating that pentamerization is required for ECM assembly. Furthermore, injected human TSP4 localizes to zebrafish MTJs and rescues muscle detachment and ECM assembly in Tsp4b-deficient embryos. Thus Tsp4 functions as an ECM scaffold at MTJs, with potential therapeutic uses in tendon strengthening and repair.

Tendon injuries are commonly encountered in the clinic, disrupting the patient's normal work/life routine and damaging the career life of athletes. Currently, there is still no effective treatment for tendon injury. Tendon tissue engineering appears to be a promising route for tendon repair and regeneration. However, current strategies utilized in research are still far away from clinical applications due to unsuccessful cellular differentiation to tendon/tenocytes. In this review, we focus on the current physical strategies (mechanical stimulation and extracellular matrix topography) and evaluate their roles in precise and stepwise tendon differentiation. A systematic comprehension of normal tendon development process by structure, gene profile and physical microenvironment analysis is likely suggestive for stepwise tenocyte differentiation. [ABSTRACT FROM AUTHOR]

The formation of the musculoskeletal system represents an intricate process of tissue assembly involving heterotypic inductive interactions between tendons, muscles and cartilage. An essential component of all musculoskeletal systems is the anchoring of the force-generating muscles to the solid support of the organism: the skeleton in vertebrates and the exoskeleton in invertebrates. Here, we discuss recent findings that illuminate musculoskeletal assembly in the vertebrate embryo, findings that emphasize the reciprocal interactions between the forming tendons, muscle and cartilage tissues. We also compare these events with those of the corresponding system in the Drosophila embryo, highlighting distinct and common pathways that promote efficient locomotion while preserving the form of the organism. [ABSTRACT FROM AUTHOR]

Abstract: MEF2 transcription factors are well-established regulators of muscle development. In this report, we describe the cloning of multiple splicing isoforms of the XMEF2A and XMEF2C encoding genes, differentially expressed during Xenopus development. Using whole-mount in situ hybridization, we found that the accumulation of XMEF2C mRNA in the tadpole stages was restricted to intersomitic regions and to the peripheral edges of hypaxial and cranial muscle masses in contrast to XMEF2A and XMEF2D, characterized by a continuous muscle cell expression. The XMEF2C positive cells express the bHLH transcription factor, Xscleraxis, known as a specific marker for tendons. Gain of function experiments revealed that the use of a hormone-inducible XMEF2C construct is able to induce Xscleraxis expression. Furthermore, XMEF2C specifically cooperates with Xscleraxis to induce tenascin C and betaig-h3, two genes preferentially expressed in Xenopus larval tendons. These findings 1) highlight a previously unappreciated and specific role for XMEF2C in tendon development and 2) identify a novel gene transactivation pathway where MEF2C cooperates with the bHLH protein, Xscleraxis, to activate specific gene expression. [Copyright &y& Elsevier]

The plantaris longus tendon of the bullfrog is a pressure-bearing tendon and develops a fibrocartilage-like arrangement in the area subjected to compressive forces. The fibrocartilage-like tissue shows some distinct aspects of cellular and fibrillar structure and distribution as compared to the mammalian counterparts. In this work, the development of the plantaris longus tendon was assessed by investigating some of its structural, cytochemical and immunocytochemical aspects in developing tadpoles. The pressure-bearing region is structurally distinct from the tension region as early as at stage 35 of larval development. There is little extracellular matrix in both regions, but the former shows round mesenchymal-like cells with many processes and cell junctions, while the latter is populated by fibroblasts. As development proceeds, the cells in the compression region retract the processes, loose the connections to each other, become rounded and produce abundant proteoglycans and some collagen fibers. Progressively, their organelles become localized in a restricted perinuclear area and are surrounded by a constantly increasing amount of vimentin. The fibroblasts of the tension region produce mostly collagen fibrils, which are packed and aligned to each other. These cells become more elongated and show a diminished cytoplasmic area. The results allow for the conclusion that the compression region does not arise by simple hyperplasia of the peripheral layers of a normal tendon, but from a programmed sequence of developmental steps. This assumption is based on the fact that muscle fibers are still developing when the tendon is already showing a differentiated compression region. We further suggest that mechanical stimulation is a secondary factor most likely associated with the maintenance of the differentiated phenotype of this tendon. [ABSTRACT FROM AUTHOR]

The transcription factor scleraxis (SCX) is expressed throughout tendon development and plays a key role in directing tendon wound healing. However, little is known regarding its role in fetal or young postnatal tendons, stages in development that are known for their enhanced regenerative capabilities. Here we used RNA-sequencing to compare the transcriptome of adult and fetal tenocytes following SCX knockdown. SCX knockdown had a larger effect on gene expression in fetal tenocytes, affecting 477 genes in comparison to the 183 genes affected in adult tenocytes, indicating that scleraxis-dependent processes may differ in these two developmental stages. Gene ontology, network and pathway analysis revealed an overrepresentation of extracellular matrix (ECM) remodelling processes within both comparisons. These included several matrix metalloproteinases, proteoglycans and collagens, some of which were also investigated in SCX knockdown tenocytes from young postnatal foals. Using chromatin immunoprecipitation, we also identified novel genes that SCX differentially interacts with in adult and fetal tenocytes. These results indicate a role for SCX in modulating ECM synthesis and breakdown and provide a useful dataset for further study into SCX gene regulation. Unlabelled Image • Scleraxis-dependent gene expression is differentially controlled in adult and fetal tenocytes. • Scleraxis knockdown results in changes in extracellular matrix remodelling genes. • Chromatin immunoprecipitation reveals novel downstream target genes which scleraxis directly regulates. [ABSTRACT FROM AUTHOR]

Proper development of tendons is crucial for the integration and function of the musculoskeletal system. Currently little is known about the molecular mechanisms controlling tendon development and tendon cell differentiation. The transcription factor Scleraxis (Scx) is expressed throughout tendon development and plays essential roles in both embryonic tendon development and adult tendon healing, but few direct target genes of Scx in tendon development have been reported and genome-wide identification of Scx direct target genes in vivo has been lacking. In this study, we have generated a Scx Flag elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new cis- elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new Scx embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Scx -/- embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Fmod , Kera , Htra3 , Ssc5d , Tnmd hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The Zfp185 , by in situ hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The Scx Flag mice provide a valuable new tool for unraveling the molecular mechanisms involving Scx in the protein interaction and gene-regulatory networks underlying many developmental and disease processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Xu, Lan, Lim and Jiang.)

As dense connective tissues connecting bone to muscle and bone to bone, respectively, tendon and ligament (T/L) arise from the somitic mesoderm, originating in a recently discovered somitic compartment, the syndetome. Inductive signals from the adjacent sclerotome and myotome upregulate expression of Scleraxis, a key transcription factor for tenogenic and ligamentogenic differentiation. Understanding T/L development is critical to establishing a knowledge base for improving the healing and repair of T/L injuries, a high-burden disease due to the intrinsically poor natural healing response. Current treatment of the three most common tendon injuries-tearing of the rotator cuff of the shoulder, flexor tendon of the hand, and Achilles tendon-include mostly surgical repair and/or conservative approaches, including biophysical modalities such as rehabilitation and cryotherapy. Unfortunately, the fibrovascular scar formed during healing possesses inferior mechanical and biochemical properties, resulting in compromised tissue functionality. Regenerative approaches have sought to augment the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation to improve the natural healing response. The key challenges in restoring full T/L function following injury include optimal combination of these biological agents as well as their delivery to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple biofactors with high spatiotemporal resolution and specificity, should lead to regenerative procedures that more closely recapitulate T/L morphogenesis, thereby offering future patients the prospect of T/L regeneration, as opposed to simple tissue repair., (Copyright © 2013 Wiley Periodicals, Inc.)