Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling

Abstract

Rotator cuff tear (RCT) is a common tendon injury, but the mechanisms of tendon healing remain incompletely understood. Elucidating the molecular mechanisms of tenogenic differentiation is essential to develop novel therapeutic strategies in clinical treatment of RCT. The long noncoding RNA H19 plays a regulatory role in tenogenic differentiation and tendon healing, but its detailed mechanism of action remains unknown. To elucidate the role of H19 in tenogenic differentiation and tendon healing, tendon-derived stem cells were harvested from the Achilles tendons of Sprague Dawley rats and a rat model of cuff tear was established for the exploration of the function of H19 in promoting tenogenic differentiation. The results showed that H19 overexpression promoted, while H19 silencing suppressed, tenogenic differentiation of tendon-derived stem cells (TDSCs). Furthermore, bioinformatic analyses and a luciferase reporter gene assay showed that H19 directly targeted and inhibited miR-140-5p to promote tenogenic differentiation. Further, inhibiting miR-140-5p directly increased VEGFA expression, revealing a novel regulatory axis between H19, miR-140-5p, and VEGFA in modulating tenogenic differentiation. In rats with RTC, implantation of H19-overexpressing TDSCs at the lesion promoted tendon healing and functional recovery. In general, the data suggest that H19 promotes tenogenic differentiation and tendon-bone healing by targeting miR-140-5p and increasing VEGFA levels. Modulation of the H19/miR-140-5p/VEGFA axis in TDSCs is a new potential strategy for clinical treatment of tendon injury.

VEGFA-Enriched Exosomes from Tendon-Derived Stem Cells Facilitate Tenocyte Differentiation, Migration, and Transition to a Fibroblastic Phenotype

“…In addition, induction of VEGFA expression by engineered nanoparticles promotes tendon healing. In our previous study, we showed that the long noncoding RNA H19 accelerates differentiation of rat tenocytes by inhibiting miR-140-5p, which leads to upregulation of VEGFA at the lesion site [31]. Expanding on this finding, we demonstrated here that upregulation of VEGFA in exosomes from TDSCs promotes tenocyte development.…”

“…Rotator cuff tendon tissues were isolated from SD rats as reported previously [31]. Tissues were sliced into small pieces, dispersed, and cultured in 6-well plates with Dulbecco's Modified Eagle Medium (DMEM, #11965092; Gibco, Waltham, MA, USA) supple-mented with 10% fetal bovine serum (FBS, #10100147C, Gibco), 100 U/ml penicillin (#10378016, Gibco), and 100 U/ml streptomycin (#10378016, Gibco) in a humidified 5% CO 2 incubator at 37 °C for 5 days.…”

Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside

“…Subsequently, the differentiation status and the clinical outcomes can be correlated. Based on this, tendon cells can be engineered to specific differentiation status by biochemical or biomechanical means prior to implantation to maximise the therapeutic effect [103,174,175]. These clinical and biological studies will be favourable in providing an insight into the treatment efficacy orchestrated by the differentiation status of tendon cells and also assist in developing a guideline for tendon-derived cell therapy with potential for individual patient customisation (Fig.…”

Irisin promotes the proliferation and tenogenic differentiation of rat tendon-derived stem/progenitor cells via activating YAP/TAZ

“…TSPCs exhibit spontaneous tenogenic differentiation potentials in vitro (Shin et al 2020 ; Liu et al 2021 ). It has been recently demonstrated that the erroneous differentiation of TSPCs to non-tenocytes is involved in the pathogenesis of chronic tendinopathy (Lui and Chan 2011 ).…”