The cellular basis of fibrotic tendon healing: challenges and opportunities

Abstract

Tendon injuries are common and can dramatically impair patient mobility and productivity, resulting in a significant socioeconomic burden and reduced quality of life. Because the tendon healing process results in the formation of a fibrotic scar, injured tendons never regain the mechanical strength of the uninjured tendon, leading to frequent re-injury. Many tendons are also prone to the development of peritendinous adhesions and excess scar formation, which further reduce tendon function and lead to chronic complications. Despite this, there are currently no treatments that adequately improve the tendon healing process due in part to a lack of information regarding the contributions of various cell types to tendon healing and how their activity may be modulated for therapeutic value. In this review, we summarize recent efforts to identify and characterize the distinct cell populations involved at each stage of tendon healing. In addition, we examine the mechanisms through which different cell populations contribute to the fibrotic response to tendon injury, and how these responses can be affected by systemic factors and comorbidities. We then discuss gaps in our current understanding of tendon fibrosis and highlight how new technologies and research areas are shedding light on this clinically important and intractable challenge. A better understanding of the complex cellular environment during tendon healing is crucial to the development of new therapies to prevent fibrosis and promote tissue regeneration.

The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

“…Tendons are known to withstand substantial mechanical loads, yet various daily activities can cause chronic microdamage or acute injury to tendons . The healing response, especially of adult tendon, is insufficient to regenerate the tissue in situ as seen by scar formation at the site of injury that can result in chronic functional tendon deficiency . Understanding the contribution of tendon‐resident cells, their PCM, and the ECM that they construct during tendon development and homeostasis has important implications for tendon regeneration.…”

“…Temporally controlled conditional deletions of these ECM components would address at which stage these proteins are required for tendon homeostasis and such studies already revealed distinct postnatal functions for biglycan and decorin . Lineage tracing experiments over the past several years made it abundantly clear that tendon tissue is host to more than one cell type . The questions that arise here are: (i) What components of the tendon ECM do individual cell types synthesize?…”

“…183,184 The healing response, especially of adult tendon, is insufficient to regenerate the tissue in situ as seen by scar formation at the site of injury that can result in chronic functional tendon deficiency. 7 Understanding the contribution of tendon-resident cells, their PCM, and the ECM that they construct during tendon development and homeostasis has important implications for tendon regeneration. While much knowledge has been gained from knockout studies of individual genes, providing a comprehensive understanding of the temporal and spatial organization of the PCM and ECM network(s) and of the identity and lineage of the various cell types in tendon is challenging.…”

“…However, recent knockout studies in mice made it clear that ECM proteins not directly involved in collagen fibrillogenesis may play important roles in tendon physiology. For example, such ECM proteins can provide unique microenvironments to maintain the identity of the different types of tendon‐resident cells . In addition, ECM molecules or their bioactive peptides, generated by proteases, can coordinate cellular responses to microdamage and macrodamage of tendon tissue.…”

“…For example, such ECM proteins can provide unique microenvironments to maintain the identity of the different types of tendon-resident cells. 6,7 In addition, ECM molecules or their bioactive peptides, generated by proteases, can coordinate cellular responses to microdamage and macrodamage of tendon tissue. In this review, we will illustrate the complexity of tendon tissue by providing an overview of the function of the "other" 15-40% of tendon ECM proteins.…”