Loss of type III collagen has limited effect on tendon healing in young adult mice.

Tendon injuries account for considerable and escalating clinical burden. After injury, tendons heal poorly with persistent fibrovascular scar. Unlike healthy tendon which is type I collagen (COL1)-rich and highly-aligned, fibrovascular scar is type III collagen (COL3)-rich and disorganized; this compositional and organizational change has been implicated in the functional deficits resulting from tendon injury. Accordingly, COL3 is historically considered a primary driver of poor tendon healing. Given compelling evidence of COL3's role in regulating matrix structure and cell behavior, we sought to define the role of COL3 in driving physiologic/pathologic tendon healing through regulation of all phases of healing. Leveraging a mouse model of global, inducible Col3a1 knockdown, we reduced Col3a1 expression at the time of patellar tendon injury and investigated extracellular matrix, cellular, and mechanical changes at 1-, 3-, and 6-weeks post-injury. Based on data from other tissues, we hypothesized that COL3 loss would exacerbate poor tendon healing, with temporally-distinct contributions to tendon healing outcomes resulting from COL3's critical regulation of matrix organization, cell phenotype and activities, and tissue mechanics. Unexpectedly, reduction of COL3 in young adult mice did not change collagen architecture and had few, nuanced impacts on cell behavior and tissue mechanics throughout healing. These findings challenge the conventional paradigm that COL3 drives poor tendon healing outcomes and emphasize the need to identify matrix and cell mechanisms contributing to poor tendon healing. Understanding COL3's role in other injury models and lifespan contexts, including tendon development and aging, will provide more insight into its regulatory and therapeutic potential.