Cell-subpopulation alteration and FGF7 activation regulate the function of tendon stem/progenitor cells in 3D microenvironment revealed by single-cell analysis

The myotendinous junction (MTJ) is a complex and special anatomical area that connects muscles and tendons, and it is also the key to repairing tendons. Nevertheless, the anatomical structure and connection structure of MTJ, the cluster and distribution of cells, and which cells are involved in repairing the tissue are still unclear. Here, we analyzed the cell subtype distribution and function of human MTJ at single-cell level. We identified four main subtypes, including stem cell, muscle, tendon, and muscle-tendon progenitor cells (MTP). The MTP subpopulation, which remains the characteristics of stem cells and also expresses muscle and tendon marker genes simultaneously, may have the potential for bidirectional differentiation. We also found the muscle-tendon progenitor cells were distributed in the shape of a transparent goblet; muscle cells first connect to the MTP and then to the tendon. And after being transplanted in the MTJ injury model, MTP exhibited strong regenerative capability. Finally, we also demonstrated the importance of mTOR signaling for MTP maintenance by in vitro addition of rapamycin and in vivo validation using mTOR-ko mice. Our research conducted a comprehensive analysis of the heterogeneity of myotendinous junction, discovered a special cluster called MTP, provided new insights into the biological significance of myotendinous junction, and laid the foundation for future research on myotendinous junction regeneration and restoration.

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“…Histologic sections (7 mm or 10 mm) for were prepared. As previously described [32], hematoxylin andeosin (H&E) staining was performed. 5.5.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Discovery of Muscle-Tendon Progenitor Subpopulation in Human Myotendinous Junction at Single-Cell Resolution

Yan

Zhang

et al. 2022

Research

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“…25 The authors also showed that FGF7 served as a novel tenogenic regulator for tendon repair and regeneration when using TSPCs in a rat patellar tendon injury model. 25 Tendon injuries involve alterations of the extracellular matrix, resulting in a profibrotic environment. 45 The outcome of adult tendon repair has been shown to result in disorganized tissues, diminished mechanical properties, and scar formation.…”

Section: Discussionmentioning

confidence: 97%

“…FGF7 is a growth factor that plays a vital role in the morphogenesis of epithelium, epithelial wound repair, and early lung development. [24][25][26] Periostin (Postn) functions as a ligand for integrin and is an extracellular matrix protein involved in wound healing and ventricular remodeling. [27][28][29][30] Periostin (Postn) is a crucial extracellular remodeling factor that plays a major role in adult cardiac remodeling diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Two genes (FGF7 and Postn) were detected with significantly increased expression in chordae tendineae. FGF7 is a growth factor that plays a vital role in the morphogenesis of epithelium, epithelial wound repair, and early lung development 24–26 27–30 …”

Section: Discussionmentioning

confidence: 99%

“…In 2022, Zhang et al conducted a study that revealed that activated FGF7 signaling can enhance tenogenesis in human TSPCs through cell–cell interactions 25 . The authors also showed that FGF7 served as a novel tenogenic regulator for tendon repair and regeneration when using TSPCs in a rat patellar tendon injury model 25 …”

Section: Discussionmentioning

confidence: 99%

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Gene expression of Postn and FGF7 in canine chordae tendineae and their effects on flexor tenocyte biology

Ren,

Wan,

Zhao

et al. 2023

Journal Orthopaedic Research

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Chordae tendineae, referred to as heart tendinous cords, act as tendons connecting the papillary muscles to the valves in the heart. Their role is analogous to tendons in the musculoskeletal system. Despite being exposed to millions of cyclic tensile stretches over a human's lifetime, chordae tendineae rarely suffer from overuse injuries. On the other hand, musculoskeletal tendinopathy is very common and remains challenging in clinical treatment. The objective of this study was to investigate the mechanism behind the remarkable durability and resistance to overuse injuries of chordae tendineae, as well as to explore their effects on flexor tenocyte biology. The messenger RNA expression profiles of chordae tendineae were analyzed using RNA sequencing and verified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Interestingly, we found that periostin (Postn) and fibroblast growth factor 7 (FGF7) were expressed at significantly higher levels in chordae tendineae, compared to flexor tendons. We further treated flexor tenocytes in vitro with periostin and FGF7 to examine their effects on the proliferation, migration, apoptosis, and tendon‐related gene expression of flexor tenocytes. The results displayed enhanced cell proliferation ability at an early stage and an antiapoptotic effect on tenocytes, while treated with periostin and/or FGF7 proteins. Furthermore, there was a trend of promoted tenocyte migration capability. These findings indicated that Postn and FGF7 may represent novel cytokines to target flexor tendon healing. Clinical significance: The preliminary discovery leads to a novel idea for treating tendinopathy in the musculoskeletal system using specific molecules identified from chordae tendineae.

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Transcriptome‐Optimized Hydrogel Design of a Stem Cell Niche for Enhanced Tendon Regeneration

Zhang,

Rao,

Wong

et al. 2024

Advanced Materials

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Bioactive hydrogels have emerged as promising artificial niches for enhancing stem cell‐mediated tendon repair. However, a substantial knowledge gap remains regarding the optimal combination of niche features for targeted cellular responses, which often leads to lengthy development cycles and uncontrolled healing outcomes. To address this critical gap, an innovative, data‐driven materiomics strategy is developed. This approach is based on in‐house RNA‐seq data that integrates bioinformatics and mathematical modeling, which is a significant departure from traditional trial‐and‐error methods. It aims to provide both mechanistic insights and quantitative assessments and predictions of the tenogenic effects of adipose‐derived stem cells induced by systematically modulated features of a tendon‐mimetic hydrogel (TenoGel). The knowledge generated has enabled a rational approach for TenoGel design, addressing key considerations, such as tendon extracellular matrix concentration, uniaxial tensile loading, and in vitro pre‐conditioning duration. Remarkably, our optimized TenoGel demonstrated robust tenogenesis in vitro and facilitated tendon regeneration while preventing undesired ectopic ossification in a rat tendon injury model. These findings shed light on the importance of tailoring hydrogel features for efficient tendon repair. They also highlight the tremendous potential of the innovative materiomics strategy as a powerful predictive and assessment tool in biomaterial development for regenerative medicine.

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Cell-subpopulation alteration and FGF7 activation regulate the function of tendon stem/progenitor cells in 3D microenvironment revealed by single-cell analysis

Cited by 18 publications

References 55 publications

Discovery of Muscle-Tendon Progenitor Subpopulation in Human Myotendinous Junction at Single-Cell Resolution

Discovery of Muscle-Tendon Progenitor Subpopulation in Human Myotendinous Junction at Single-Cell Resolution

Gene expression of Postn and FGF7 in canine chordae tendineae and their effects on flexor tenocyte biology

Transcriptome‐Optimized Hydrogel Design of a Stem Cell Niche for Enhanced Tendon Regeneration

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