Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome
Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome
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DOI：
10.7554/elife.54383
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发表时间：
2020-09-08
期刊：
影响因子：
7.7
通讯作者：
Hetzer, Martin W.
中科院分区：
文献类型：
--
作者：
Bersini, Simone;Schulte, Roberta;Hetzer, Martin W.
血管功能障碍是多种年龄相关疾病的共同特征。然而，人体血管系统的健康和病理老化建模是一个悬而未决的实验挑战。在这里，我们通过直接重编程来自不同年龄供体和Hutchinson-Gilford早衰综合征（HGPS）患者的健康人成纤维细胞来产生诱导的血管内皮细胞（iVEC）和平滑肌细胞（iSMC）。从老年供体诱导的iVEC揭示了GSTM 1和PALD 1的上调，这些基因与氧化应激、炎症和内皮连接稳定性相关，作为血管老化标志物。对PALD 1 KD VEC进行的功能测定证明了血管通透性的恢复。我们发现，来自HGPS供体的iSMC过表达骨形态发生蛋白（BMP）-4，其在HGPS中观察到的血管钙化和内皮屏障损伤中起关键作用。引人注目的是，来自HGPS的血清中的BMP 4浓度高于来自年龄匹配的小鼠的血清中的BMP 4浓度。此外，用阻断抗体靶向BMP 4恢复了体外血管屏障的功能，因此代表了限制HGPS心血管功能障碍的潜在未来治疗策略。这些结果表明，iVEC和iSMC保留了疾病相关的特征，允许在体外对血管老化和HGPS进行建模。
Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP)-4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age -matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.