The Cellular Basis of Fibrotic Tendon Healing: Now in Higher Definition

Tendon injuries are common and heal through the formation of a fibrotic scar rather than regeneration. This poor natural healing results in impaired function and increases the risk of re-injury. In 2019, we reviewed the current state of the field's understanding of the cellular basis of fibrotic tendon healing, focusing on the resident and infiltrating cell populations that appear at key stages and what was known about their role in tendon healing at the time. Since then, advances in transcriptomic technologies and wide-spread adoption of lineage tracing have refined our understanding of these processes. This updated review reexamines the key cellular players in tendon healing and summarizes new studies into their origins, dynamics, and potential interactions during healing. Specifically, we highlight recent insights into peripheral compartmental complexity, fibroblast heterogeneity, the emerging role of the adaptive immune system, and potential cellular crosstalk in both tendon homeostasis and healing. We also discuss potential therapeutic targets aimed at modulating cell behavior to reduce fibrosis while promoting tendon regeneration and highlight new gaps in knowledge that are critical for continued progress in the field. This review serves as an updated guide to understanding the cellular drivers of fibrotic tendon healing and for informing the development of new therapeutic strategies to improve tendon healing outcomes.