Department of Biomedical Engineering, Schools of Engineering and Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Robert Berne Cardiovascular Research Center, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Sci Adv. 2024 Jun 14;10(24):eadf2675. doi: 10.1126/sciadv.adf2675.
Fibrosis-associated fibroblasts have been identified across various fibrotic disorders, but not in the context of biomaterials, fibrotic encapsulation, and the foreign body response. In other fibrotic disorders, a fibroblast subpopulation defined by Thy-1 loss is strongly correlated with fibrosis yet we do not know what promotes Thy-1 loss. We have previously shown that Thy-1 is an integrin regulator enabling normal fibroblast mechanosensing, and here, leveraging nonfibrotic microporous annealed particle (MAP) hydrogels versus classical fibrotic bulk hydrogels, we demonstrate that mice mount a fibrotic response to MAP gels that includes inflammatory signaling. We found that a distinct and cryptic α-smooth muscle actin-positive Thy-1 fibroblast population emerges in response to interleuklin-1β (IL-1β) and tumor necrosis factor-α (TNFα). Furthermore, IL-1β/TNFα-induced Thy-1 fibroblasts consist of two distinct subpopulations that are strongly proinflammatory. These findings illustrate the emergence of a unique proinflammatory, profibrotic fibroblast subpopulation that is central to fibrotic encapsulation of biomaterials.
纤维化相关成纤维细胞已在多种纤维化疾病中被鉴定出来，但尚未在生物材料、纤维化包裹和异物反应的背景下进行研究。在其他纤维化疾病中，一个由 Thy-1 缺失定义的成纤维细胞亚群与纤维化强烈相关，但我们不知道是什么促进了 Thy-1 的缺失。我们之前已经表明，Thy-1 是一种整合素调节剂，能够使正常成纤维细胞进行机械感知，在这里，我们利用非纤维化的微孔退火颗粒（MAP）水凝胶与经典的纤维化块状水凝胶相比，证明了 小鼠对 MAP 凝胶会产生纤维化反应，包括炎症信号。我们发现，在白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNFα）的作用下，一种独特的、隐匿的α-平滑肌肌动蛋白阳性 Thy-1 成纤维细胞群体出现。此外，IL-1β/TNFα 诱导的 Thy-1 成纤维细胞由两个截然不同的强烈促炎的亚群组成。这些发现说明了一种独特的促炎、促纤维化成纤维细胞亚群的出现，这对于生物材料纤维化包裹至关重要。
