Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis.
Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis.
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DOI：
10.1038/s41598-020-72875-x
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发表时间：
2020-09-25
影响因子：
4.6
通讯作者：
Yates PA
中科院分区：
文献类型：
--
作者：
Ray HC;Corliss BA;Bruce AC;Kesting S;Dey P;Mansour J;Seaman SA;Smolko CM;Mathews C;Dey BK;Owens GK;Peirce SM;Yates PA
视网膜疾病的特征通常是在整个神经视网膜上发现过多的疤痕组织。然而，视网膜纤维化的病理生理学机制仍然知之甚少，导致纤维化反应的细胞类型也不完全确定。在这里，我们表明，肌成纤维细胞分化的壁细胞直接导致视网膜纤维化。利用系谱追踪技术，我们证明了化学眼损伤后，MYH11+的壁细胞从视网膜微血管系统中分离出来，并分化为肌成纤维细胞，形成视网膜前膜。抑制转化生长因子β受体可减少MYH11+视网膜壁细胞肌成纤维细胞的分化，并减少随后在视网膜表面形成的瘢痕组织。我们展示了氧诱导视网膜病变的小鼠模型中的视网膜纤维化，这是由于玻璃体内注射脂肪MYH11来源的间充质干细胞，以及随后的肌成纤维细胞分化所致。在这个模型中，抑制转化生长因子β受体信号不会显著改变视网膜内肌成纤维细胞的分化和胶原的分泌。这项工作显示了视网膜纤维化的复杂性，其中瘢痕的形成受到转化生长因子β受体和非转化生长因子β受体依赖的过程的调节，涉及壁细胞和衍生的间充质干细胞。它还对一旦将外源性MSCs注入临床患者的玻璃体内后潜在的有害的、促纤维化的作用提出了警告。
Retinal diseases are frequently characterized by the accumulation of excessive scar tissue found throughout the neural retina. However, the pathophysiology of retinal fibrosis remains poorly understood, and the cell types that contribute to the fibrotic response are incompletely defined. Here, we show that myofibroblast differentiation of mural cells contributes directly to retinal fibrosis. Using lineage tracing technology, we demonstrate that after chemical ocular injury, Myh11+ mural cells detach from the retinal microvasculature and differentiate into myofibroblasts to form an epiretinal membrane. Inhibition of TGFβR attenuates Myh11+ retinal mural cell myofibroblast differentiation, and diminishes the subsequent formation of scar tissue on the surface of the retina. We demonstrate retinal fibrosis within a murine model of oxygen-induced retinopathy resulting from the intravitreal injection of adipose Myh11-derived mesenchymal stem cells, with ensuing myofibroblast differentiation. In this model, inhibiting TGFβR signaling does not significantly alter myofibroblast differentiation and collagen secretion within the retina. This work shows the complexity of retinal fibrosis, where scar formation is regulated both by TGFβR and non-TGFβR dependent processes involving mural cells and derived mesenchymal stem cells. It also offers a cautionary note on the potential deleterious, pro-fibrotic effects of exogenous MSCs once intravitreally injected into clinical patients.
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