Abstract
The interfascicular matrix (IFM) binds tendon fascicles and contains a population of morphologically distinct cells. However, the role of IFM-localised cell populations in tendon repair remains to be determined. The basement membrane protein laminin-α4 also localises to the IFM. Laminin-α4 is a ligand for several cell surface receptors, including CD146, a marker of pericyte and progenitor cells. We used a needle injury model in the rat Achilles tendon to test the hypothesis that the IFM is a niche for CD146+ cells that are mobilised in response to tendon damage. We also aimed to establish how expression patterns of circulating non-coding RNAs alter with tendon injury and identify potential RNA-based markers of tendon disease. The results demonstrate the formation of a focal lesion at the injury site, which increased in size and cellularity for up to 21 days post injury. In healthy tendon, CD146+ cells localised to the IFM, compared with injury, where CD146+ cells migrated towards the lesion at days 4 and 7, and populated the lesion 21 days post injury. This was accompanied by increased laminin-α4, suggesting that laminin-α4 facilitates CD146+ cell recruitment at injury sites. We also identified a panel of circulating microRNAs that are dysregulated with tendon injury. We propose that the IFM cell niche mediates the intrinsic response to injury, whereby an injury stimulus induces CD146+ cell migration. Further work is required to fully characterise CD146+ subpopulations within the IFM and establish their precise roles during tendon healing.
Highlights
Tendons consist of highly aligned, collagen-rich fascicles bound together by a looser, less organised interfascicular matrix (IFM; referred to as the endotenon)
Sci. 2021, 22, 9729 that wounds caused by 23G needles healed rapidly and were difficult to detect by histology 7 days post injury, whereas those caused by 19G needles resulted in damage towards the peripheral margins of the tendon as well as the central fibres and were less consistent between individuals (Figure S1)
We have optimised and characterised a simple, reproducible model of injury in the rat Achilles tendon. This model demonstrates that proteins expressed within the IFM in healthy tendon are present within needle-induced lesions, suggesting that IFM-localised cells migrate to populate sites of injury
Summary
Tendons consist of highly aligned, collagen-rich fascicles bound together by a looser, less organised interfascicular matrix (IFM; referred to as the endotenon). Our previous work established that the IFM plays an important mechanical role in tendon, allowing for sliding between fascicles and providing the tendon with additional extensibility [1,2,3]. These properties are provided by structural proteins, including elastin and lubricin [4,5,6,7]. The production and replacement of these components by IFM resident cells is likely critical to maintain tendon function. IFM cell populations are, likely key contributors to maintaining tendon homeostasis and responding to injury. While it is evident that the IFM houses a population of cells that are morphologically distinct and present at a higher density compared to the elongated tenocytes resident within the fascicles [10], the roles of IFM-localised cell populations in tendon maintenance and repair remain largely undefined
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