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 reinjury. 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.

Figure 1.. Illustration of the various cell populations during the phases of tendon healing.

Tendons contain a number of resident tendon cell sub-populations during homeostasis, including scleraxis (Scx)+ cells, S100a4+ cells, Scx+S100a4+ cells, and Scx+ alpha smooth muscle actin (αSMA)+ cells. Macrophages have also been reported in normal tendon, along with the presence of a tendon/stem progenitor population. There are likely additional resident cell sub-populations that have yet to be identified, and the relationships between those identified here (with respect to lineage or origin) are currently unknown. Shortly following injury, resident tendon cells directly adjacent to the injury site appear to undergo apoptosis. Neutrophils arrive, followed shortly by both M1 and M2 macrophages, as well as other bone-marrow derived cells whose identity and fate are currently unknown. During the fibroblastic/proliferative phase, epitenon cells close to the injury proliferate, and Scx+ cells that appear to originate from the epitenon migrate into the scar area, forming an organized bridging tissue between the two opposing ends of the tendon while S100a4+ and αSMA+ cells are found throughout the scar tissue. S100a4+ and αSMA+ cells during this phase appear to be derived from both intrinsic as well as extrinsic sources and likely represent heterogenous populations. Of the healing phases, the remodeling phase is the least characterized due to significant differences in the duration between tendons and injury models. During this phase, tissue continuity is restored, however the scar tissue remains disorganized compared to native tendon. It is currently unknown whether the phenotypes and relative abundance of tendon cell sub-populations remain altered or return to their pre-injury states and to what extent these potential changes in cell population may affect tendon function.