Abstract
To better understand the molecular mechanisms of tendon healing, we investigated the Murphy Roth’s Large (MRL) mouse, which is considered a model of mammalian tissue regeneration. We show that compared to C57Bl/6J (C57) mice, injured MRL tendons have reduced fibrotic adhesions and cellular proliferation, with accelerated improvements in biomechanical properties. RNA-seq analysis revealed that differentially expressed genes in the C57 healing tendon at 7 days post injury were functionally linked to fibrosis, immune system signaling and extracellular matrix (ECM) organization, while the differentially expressed genes in the MRL injured tendon were dominated by cell cycle pathways. These gene expression changes were associated with increased α-SMA+ myofibroblast and F4/80+ macrophage activation and abundant BCL-2 expression in the C57 injured tendons. Transcriptional analysis of upstream regulators using Ingenuity Pathway Analysis showed positive enrichment of TGFB1 in both C57 and MRL healing tendons, but with different downstream transcriptional effects. MRL tendons exhibited of cell cycle regulatory genes, with negative enrichment of the cell senescence-related regulators, compared to the positively-enriched inflammatory and fibrotic (ECM organization) pathways in the C57 tendons. Serum cytokine analysis revealed decreased levels of circulating senescence-associated circulatory proteins in response to injury in the MRL mice compared to the C57 mice. These data collectively demonstrate altered TGFB1 regulated inflammatory, fibrosis, and cell cycle pathways in flexor tendon repair in MRL mice, and could give cues to improved tendon healing.
Highlights
Flexor tendons transmit the intricate muscle forces required to move the digits freely
The synovial space was significantly increased in the Murphy Roth’s Large (MRL) tendon at 14 and 28 dpi compared to the C57 tendons (Fig. 1K), while the cross sectional area of the MRL tendons was significantly larger than the C57 tendon at all time points (Fig. 1L)
Previous studies demonstrate that MRL tendon injuries heal to near normal biomechanical p roperties[25], have reduced infiltrating immune c ells[25], attenuated inflammatory expression[24,36], lower catabolic enzyme a ctivity[28], heightened matrix metalloproteinases (MMPs) a ctivity[24], and improved extracellular matrix (ECM) a lignment[26]
Summary
Flexor tendons transmit the intricate muscle forces required to move the digits freely These hierarchically structured and tightly aligned collagen-rich connective tissues are sparsely populated and maintained by tenocytes, which are fibroblast-like cells that express phenotypic transcriptional factors including scleraxis (Scx)[1,2], mohawk (Mkx)[3,4], the tendon matrix protein of collagen type I (Col1), and non-collagenous proteins such as the glycoprotein tenomodulin (Tnmd)[5,6]. More recent studies injured the patellar tendon with a 0.75 mm tendon mid-substance biopsy punch and again demonstrated that MRL patellar tendons heal to near native biomechanical properties with an attenuated inflammatory response, heightened MMP activity, and improved ECM alignment[24,26]. Our transcriptional analysis suggests that these biological effects are related to altered TGFB1 regulated gene sets negatively enriching cell cycle and senescence transcriptional pathways in the MRL tendons, and positively enriching inflammatory and ECM organization pathways in the C57 tendons
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