Widespread diversity in the transcriptomes of functionally divergent limb tendons

Abstract

Key points Tendon is a hypocellular, matrix‐rich tissue that has been excluded from comparative transcriptional atlases. These atlases have provided important knowledge about biological heterogeneity between tissues, and our study addresses this important gap. We performed measures on four of the most studied tendons, the Achilles, forepaw flexor, patellar and supraspinatus tendons of both mice and rats. These tendons are functionally distinct and are also among the most commonly injured, and therefore of important translational interest. Approximately one‐third of the filtered transcriptome was differentially regulated between Achilles, forepaw flexor, patellar and supraspinatus tendons within either mice or rats. Nearly two‐thirds of the transcripts that are expressed in anatomically similar tendons were different between mice and rats. The overall findings from this study identified that although tendons across the body share a common anatomical definition based on their physical location between skeletal muscle and bone, tendon is a surprisingly genetically heterogeneous tissue. Abstract Tendon is a functionally important connective tissue that transmits force between skeletal muscle and bone. Previous studies have evaluated the architectural designs and mechanical properties of different tendons throughout the body. However, less is known about the underlying transcriptional differences between tendons that may dictate their designs and properties. Therefore, our objective was to develop a comprehensive atlas of the transcriptome of limb tendons in adult mice and rats using systems biology techniques. We selected the Achilles, forepaw digit flexor, patellar, and supraspinatus tendons due to their divergent functions and high rates of injury and tendinopathies in patients. Using RNA sequencing data, we generated the Comparative Tendon Transcriptional Database (CTTDb) that identified substantial diversity in the transcriptomes of tendons both within and across species. Approximately 30% of filtered transcripts were differentially regulated between tendons of a given species, and nearly 60% of the filtered transcripts present in anatomically similar tendons were different between species. Many of the genes that differed between tendons and across species are important in tissue specification and limb morphogenesis, tendon cell biology and tenogenesis, growth factor signalling, and production and maintenance of the extracellular matrix. This study indicates that tendon is a surprisingly heterogenous tissue with substantial genetic variation based on anatomical location and species.

Scleraxis is required for the growth of adult tendons in response to mechanical loading

“…We only studied male mice, as we previously demonstrated a general lack of differences between the Achilles tendons of male and female mice (36), and we anticipate the results are likely applicable to both sexes. Results from the plantaris tendon may not be applicable to all tendons, as different tendons display extensive divergence in their function and transcriptional profiles (37). Only 2 time points were used following overload to study scleraxis function.…”

Tendon Stem/Progenitor Cell Subpopulations and Their Implications in Tendon Biology

“…It must however be noted that viable markers for the identification of TSPCs in vitro are not necessarily useful for tracking TSPCs in situ . Tendon tissues across the body and between different species differ in architecture, biomechanics and transcriptome ( Disser et al, 2020 ). Much caution should be exercised in classifying TSPCs subpopulations, considering the influence of different cell sources and contamination.…”

Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies

“…To complicate the issue further, transcriptional heterogeneity across different tendons and within tenocytes has been reported. 142,147,148 For instance, Bglap was reported to be a reliable marker of adult tendon sheaths in mice, 139 but was not detected within the adult patellar tendon sheath. 125 Whether and to what extent these differences are important for tendon development, function, and repair remains relatively uncharacterized.…”