Induced Pluripotent Stem Cells in Pulmonary Arterial Hypertension.
Induced Pluripotent Stem Cells in Pulmonary Arterial Hypertension.
复制标题
肺动脉高压中的诱导多能干细胞。
DOI：
10.1164/rccm.201610-2111ed
复制
发表时间：
2017
影响因子：
24.7
通讯作者：
Yan,Ling
中科院分区：
文献类型：
--
作者：
Hamid,Rizwan;Yan,Ling
Yamanaka小组的开创性工作表明，过表达四种转录因子，八聚体结合蛋白4 (OCT4), kr<s:1> ppel样因子4 (KLF4)，性别决定区Y-box 2 （SOX2）和c-myc禽髓细胞瘤病毒致癌基因同源物（c-myc），可以将体细胞重编程为诱导多能干细胞（iPSCs），然后可以分化为所有细胞类型(1)。自从这一发现以来，iPSCs作为疾病模型、药物发现和基于细胞的治疗策略测试的巨大前景已经变得清晰起来。肺部疾病是全世界发病率和死亡率的主要原因之一。对于终末期肺部疾病患者，目前可用的治疗只能在有限的时间范围内缓解症状或延缓疾病进展。肺动脉高压（PAH）是肺微血管、循环细胞和右心的复杂疾病，预后较差（2,3）。多环芳烃的动物模型已经存在了一段时间，并为疾病的发病机制提供了关键的见解。然而，试图将这些发现转化为对患者的治疗，充其量也是不完美的，因为在分子水平上，动物的肺和肺组织与人类的肺和肺组织不同，因此很难在体外重现疾病过程。使用人类肺细胞可以解决其中的一些缺陷。然而，在技术上很难分离和表征足够数量的人类细胞以用于实验室研究。多能干细胞为这个问题提供了一个潜在的解决方案。iPSCs已被用于衍生呼吸道上皮细胞、血管内皮细胞和血管平滑肌细胞（4 - 6），也被用于研究肺发育和血管建模（4,7 - 9）。然而，它们是否可以作为研究PAH新治疗剂潜力的工具尚不清楚。在这一期的杂志上，Sa和他的同事（第930-941页）提出了原则性研究的数据，这些研究解决了一个重要的问题：来自PAH患者的iPSCs是否有潜力作为药物发现和测试的工具（10）。他们比较了从特发性或遗传性PAH患者分离的肺动脉内皮细胞与从同一患者的成纤维细胞衍生的iPSCs中提取的内皮细胞（ECs）。作者发现，iPSC-ECs与天然肺动脉内皮细胞在形态、功能缺陷、骨形态发生蛋白受体(BMPR)-II信号的减少，以及对骨形态发生蛋白9刺激和药物治疗的反应等方面存在许多相似之处，但也存在一些差异。通过RNA-seq分析，他们进一步确定了导致天然ECs和iPSC-ECs之间所观察到的功能和药物反应差异的分子特征。总之，他们的数据表明，ipsc衍生的内皮细胞可以在功能和药物发现研究中作为天然内皮细胞的替代品。他们的工作表明，iPSC-ECs模型有潜力作为一种精确/个性化的医疗工具，以确定众多药物中的哪一种对特定患者有效，因为这些细胞来自最终接受药物治疗的同一患者。虽然这个概念可能令人兴奋，但他们的数据也表明，这些细胞的使用并不简单，在做出广泛推广的结论之前，还需要更多的数据。例如，他们发现两种IPSC-ECs中只有一种来自遗传性PAH患者（具有相同的BMPR2突变），六种IPSC-ECs中只有两种来自患者……
Pioneering work by Yamanaka’s group showed that overexpression of four transcription factors, octamer-binding protein 4 (OCT4), Krüppel-like factor 4 (KLF4), sex determining region Y-box 2 (SOX2), and c-myc avian myelocytomatosis viral oncogene homolog (c-MYC), could reprogram somatic cells into induced pluripotent stem cells (iPSCs), which could then be differentiated into all cell types (1). Since that finding, it has become clear that iPSCs hold great promise as models for diseases, drug discovery, and testing of cell-based therapeutic strategies. Pulmonary diseases are one leading cause of morbidity and mortality worldwide. Currently available treatments can only alleviate symptoms or delay disease progression within a limited time range for patients with end-stage pulmonary diseases. Pulmonary arterial hypertension (PAH) is a complex disorder of pulmonary microvasculature, circulating cells, and right heart, with poor prognosis (2, 3). Animal models of PAH have existed for some time and have provided key insights into disease pathogenesis. Attempts to translate these findings into treatment for patients, however, have been imperfect at best, because at a molecular level animal lungs and lung tissues are different from human lungs and tissues, and thus it has been difficult to recapitulate the disease process in vitro. Use of human lung cells could address some of the deficiencies. However, it is technically difficult to isolate and characterize human cells in enough number to be useful in laboratory studies. iPSCs provide one potential solution to this problem. iPSCs have been used to derive respiratory epithelial cells, vascular endothelial cells, and vascular smooth muscle cells (4–6) and have also been used to study lung development and vascular modeling (4, 7–9). However, whether they can serve as tools to investigate the potential for new therapeutic agents in PAH is unknown. In this issue of the Journal, Sa and colleagues (pp. 930–941) present data from proof-of-principle studies that address an important question: whether iPSCs derived from patients with PAH have potential as tools for drug discovery and testing (10). They compared the pulmonary artery endothelial cells isolated from patients with idiopathic or heritable PAH to endothelial cells (ECs) derived from fibroblast-derived iPSCs from the same patients. The authors show that there are many similarities between the iPSC-ECs and native pulmonary artery endothelial cells, including morphology, functional deficits, reduction of bone morphogenetic protein receptor (BMPR)-II signaling, and, importantly, response to bone morphogenetic protein 9 stimulation and drug treatment, as well as some differences. Using RNA-seq analyses, they further identified molecular signatures responsible for the observed functional and drug response differences between native ECs and iPSC-ECs. In summary, their data show that iPSC-derived ECs can serve as surrogates for native ECs in both functional and drug discovery studies. Their work suggests that the iPSC-ECs model has the potential to serve as a precision/personalized medicine tool—to determine which one of the many drugs would be effective in a particular patient—because the cells are derived from the same patient who would, in the end, receive the drug. Although this concept maybe exciting, their data also show that the use of these cells is not straightforward, and additional data are needed before broadly generalizable conclusions can be made. For example, they found that only one of two IPSC-ECs derived from patients with heritable PAH (with the same BMPR2 mutation) and only two of six iPSC-ECs derived from patients …