Does erroneous differentiation of tendon-derived stem cells contribute to the pathogenesis of calcifying tendinopathy？

Calcifying tendinopathy is a tendon disorder with calcium deposits in the mid-substance presented with chronic activity-related pain, tenderness, local edema and various degrees of incapacitation. Most of current treatments are neither effective nor evidence-based because its underlying pathogenesis is poorly understood and treatment is usually symptomatic. Understanding the pathogenesis of calcifying tendlinopathy is essential for its effective evidence-based management. One of the key histopathological features of calcifying tendinopathy is the presence of chondrocyte phenotype which surrounds the calcific deposits, suggesting that the formation of calcific deposits was cellmediated.Although the origin of cells participating in the formation of chondrocyte phenotype and ossification is still unknown, many evidences have suggested that erroneous tendon cell differentiation is involved in the process. Recent studies have shown the presence of stem cells with self-renewal and multi-differentiation potential in human,horse, mouse and rat tendon tissues. We hypothesized that the erroneous differentiation of tendon-derived stem cells （TDSCs） to chondrocytes or osteoblasts leads to chondrometaplasia and ossification and hence weaker tendon, failed healing and pain, in calcifying tendinopathy. We present a hypothetical model on the pathogenesis and evidences to support this hypothesis. Understanding the key role of TDSCs in the pathogenesis of calcifying tendinopathy and the mechanisms contributing to their erroneous differentiation would provide new opportunities for the management of calcifying tendinopathy. The re-direction of the differentiation of resident TDSCs to tenogenic or supplementation of MSCsprogrammed for tenogenic differentiation may be enticing targets for the management of calcifying tendinopathy in e future.

Overexpression of mechanical sensitive miR-337-3p alleviates ectopic ossification in rat tendinopathy model via targeting IRS1 and Nox4 of tendon-derived stem cells

Tendinopathy,which is characterized by the ectopic ossification of tendon,is a common disease occurring in certain population,such as athletes that suffer from repetitive tendon strains.However,the molecular mechanism underlying the pathogenesis of tendinopathy caused by the overuse of tendon is still lacking.Here,we found that the mechanosensitive miRNA,miR-337-3p,had lower expression under uniaxial cyclical mechanical loading in tendon-derived stem cells(TDSCs)and negatively controlled chondro-osteogenic differentiation of TDSCs.Importantly,downregulation of miR-337-3p expression was also observed in both rat and human calcified tendons,and overexpressing miR-337-3p in patellar tendons of rat tendinopathy model displayed a robust therapeutic efficiency.Mechanistically,we found that the proinflammatory cytokine interleukin-1^was the upstream factor of miR-337-3p that bridges the mechanical loading with its downregulation.Furthermore,the target genes of miR-337-3p,NADPH oxidase 4,and insulin receptor substrate 1,activated chondro-osteogenic differentiation of TDSCs through JNK and ERK signaling,respectively.Thus,these findings not only provide novel insight into the molecular mechanisms underlying ectopic ossification in tendinopathy but also highlight the significance of miR-337-3p as a putative therapeutic target for clinic treatment of tendinopathy.

Photothermal‑Triggered Structural Change of Nanofiber Scaffold Integrating with Graded Mineralization to Promote Tendon–Bone Healing

Scaffolds functionalized with graded changes in both fiber alignment and mineral content are more appealing for tendon-bone healing.This study reports the healing of rotator cuff injury using a heterogeneous nanofiber scaffold,which is associated with a structural gradating from aligned to random and an increasing gradient of mineral content in the same orientation.The photothermal-triggered structural change of a nanofiber scaffold followed by graded mineralization is key to constructing such scaffolds.This type of scaffold was found to be biocompatible and provide beneficial contact guidance in the manipulation of tendon-derived stem cell morphologies in vitro.Specifically,tenogenic and osteogenic differentiation of tendon-derived stem cells were simultaneously achieved using the fabricated scaffold.In vivo investigation also showed the improved healing of rabbit rotator cuff injuries based on immunohistochemical analysis and biomechanical investigation that indicates the promising potential of a dual-gradient nanofiber scaffold in clinical tendon-bone healing.