Widespread diversity in the transcriptomes of functionally divergent limb tendons

Abstract

r 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.r 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.r 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.r 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 Nathaniel Disser graduated in 2018 from Gonzaga University in Spokane, WA, where he obtained a Bachelor of Science degree in Human Physiology. He is now participating in a two-year Post-Baccalaureate Research Program at the Hospital for Special Surgery in New York, NY. His current research interests include studying the mechanobiology of tendon and muscle during tissue growth and repair. As an aspiring physician-scientist, he hopes to improve the understanding and treatment of debilitating musculoskeletal injuries and diseases. N. P. Disser and others J Physiol 598.8 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 indicate...

Achilles Tendons Display Region-Specific Transcriptomic Signatures Associated With Distinct Mechanical Properties

“…Distinct transcriptomic signatures in different tendons throughout the body in mice and rats have been previously identified and are likely influenced by their local biomechanical environments. 9 Similarly, the results of this study suggest an interplay between the unique transcriptomic signatures and mechanical loading history along the length of a tendon. The increasing stress observed moving distally along the length of the tendon may partially explain the etiology of acute tendon injury, as ruptures most often occur 2 to 3 cm from the enthesis.…”

“…28 These cells have historically been the focus of tendon cell biology, but recent studies using bulk and single-cell transcriptomic analysis have revealed a more heterogeneous phenotype within tendon tissue. 1,8,9 This includes identification of multiple fibroblast subpopulations, as well as other resident cells such as immune cells, sensory neurons, and endothelial cells. 1,8 In addition, tendons in different anatomic locations display distinct gene expression signatures, and this is likely influenced by the biomechanical loading environment.…”

The Micromechanical Environment of the Impinged Achilles Tendon Insertion

“…Therefore, the biological response to impingement could be detectable at early stages based on changes in the micromechanical strain environment of the PCM. Our multiphoton elastography can also be coupled with the use of transgenic mice and lineage tracing methods to understand if different tendon cell populations [37][38][39] undergo differential deformation under impingement. These studies could provide insight into cell populations that are more sensitive to impingement.…”

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 two time points were used following overload to study scleraxis function.…”