细胞周基质(PCM)是围绕细胞的特化的细胞外基质。与PCM的相互作用使细胞能够感测和响应机械信号,触发适当的自适应响应。胶原蛋白VI是肌肉和肌腱PCM的组成部分。胶原蛋白VI基因突变导致一组独特的遗传性骨骼肌疾病,和Ullrich先天性肌营养不良(UCMD)是最严重的形式。除了肌肉无力,UCMD患者显示肌腱PCM的结构和功能改变。在这项研究中,我们调查了胶原VI突变引起的PCM改变是否影响肌腱成纤维细胞对机械刺激的反应.通过利用从未受影响的供体和UCMD患者获得的人类肌腱培养物,我们分析了细胞力学传感器的形态和功能特性。我们发现UCMD细胞的初级纤毛长度比对照长。与控件不同,在UCMD细胞中,机械刺激后纤毛患病率和长度均未恢复.因此,在相同的实验条件下,Hedgehog信号通路的激活,这与纤毛活动有关,UCMD细胞受损。最后,暴露于机械刺激的UCMD肌腱细胞显示出改变的粘着斑,以及Akt的受损激活,ERK1/2,p38MAPK,和YAP下游的机械响应基因。通过探索对机械刺激的反应,第一次,我们的发现揭示了UCMD来源的肌腱成纤维细胞的病理生理学的新的未报道的机制方面,并指出了胶原蛋白VI在肌腱机械传导调节中的作用.
The pericellular matrix (PCM) is a specialized extracellular matrix that surrounds cells. Interactions with the PCM enable the cells to sense and respond to mechanical signals, triggering a proper adaptive response. Collagen VI is a component of muscle and tendon PCM. Mutations in collagen VI genes cause a distinctive group of inherited skeletal muscle diseases, and Ullrich congenital muscular dystrophy (UCMD) is the most severe form. In addition to muscle weakness, UCMD patients show structural and functional changes of the tendon PCM. In this study, we investigated whether PCM alterations due to collagen VI mutations affect the response of tendon fibroblasts to mechanical stimulation. By taking advantage of human tendon cultures obtained from unaffected donors and from UCMD patients, we analyzed the morphological and functional properties of cellular mechanosensors. We found that the length of the primary cilia of UCMD cells was longer than that of controls. Unlike controls, in UCMD cells, both cilia prevalence and length were not recovered after mechanical stimulation. Accordingly, under the same experimental conditions, the activation of the Hedgehog signaling pathway, which is related to cilia activity, was impaired in UCMD cells. Finally, UCMD tendon cells exposed to mechanical stimuli showed altered focal adhesions, as well as impaired activation of Akt, ERK1/2, p38MAPK, and mechanoresponsive genes downstream of YAP. By exploring the response to mechanical stimulation, for the first time, our findings uncover novel unreported mechanistic aspects of the physiopathology of UCMD-derived tendon fibroblasts and point at a role for collagen VI in the modulation of mechanotransduction in tendons.