Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Nat Commun. 2020 Aug 17;11(1):4110. doi: 10.1038/s41467-020-17901-2.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaMmp13 mice or LmnaMmp13 mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.
亨廷顿舞蹈病综合征（HGPS）是一种儿童早老病，可导致早逝。平滑肌细胞（SMCs）是 HGPS 个体中受影响最严重的细胞，尽管其易感性的原因仍知之甚少。在这项工作中，我们开发了一种由诱导多能干细胞（iPSCs）产生的 HGPS-SMC 形成的微流控芯片，以研究它们对流动切应力的脆弱性。在动脉流动条件下培养的 HGPS-iPSC SMC 在培养几天后会从芯片上脱落；这个过程是由金属蛋白酶 13（MMP13）的上调介导的。重要的是，LmnaMmp13 双突变小鼠或用 MMP 抑制剂治疗的 LmnaMmp13 小鼠的主动脉弓中的 SMC 损失低于对照组。MMP13 的上调似乎至少部分是由糖萼的上调介导的。我们的 HGPS-SMC 芯片代表了为 HGPS 个体开发治疗方法的平台，这些方法可能会补充以前的临床前和临床治疗。
