Reply: Expanded Role for Bone Marrow-derived Hematopoietic Stem and Progenitor Cells in Pulmonary Arterial Hypertension.
Reply: Expanded Role for Bone Marrow-derived Hematopoietic Stem and Progenitor Cells in Pulmonary Arterial Hypertension.
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答复：骨髓源性造血干细胞和祖细胞在肺动脉高压中的作用扩大。
DOI：
10.1164/rccm.201603-0611le
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发表时间：
2016
影响因子：
24.7
通讯作者：
Hamid,Rizwan
中科院分区：
文献类型：
--
作者：
Yan,Ling;West,James;Hamid,Rizwan
我们赞扬严和他的同事们(1)的出色研究，这增加了越来越多的证据表明，髓系/骨髓起源于肺动脉高压(PAH)。利用免疫活性Bmpr2突变型和野生型小鼠模型中的相互骨髓嵌合体，作者确定了在没有右室肥厚的情况下，肺小动脉肌化和右室收缩压升高的骨髓依赖机制。这一发现补充了我们之前的异种移植研究(2)，在该研究中，来自PAH患者的造血干细胞被移植到免疫低下的小鼠体内。与严和同事的工作相似(1)，来自患者的造血干细胞的植入率是来自Bmpr2突变患者的干细胞的五倍，移植来自Bmpr2突变患者的干细胞比移植突变阴性的PAH骨髓干细胞的动物更能导致血管平滑肌细胞肥大。同样重要的是，先前的研究表明，移植5-羟色胺2B受体缺陷的骨髓可以预防缺氧诱导的PAH的发展(3)，这表明髓系干细胞可以促进或阻止肺血管疾病的发展。即使在没有明显的血液异常的情况下，PAH患者的骨髓中的造血祖细胞和干细胞库也一致增加(2，4)。有趣的是，以克隆性干细胞扩增为特征的骨髓增殖性恶性肿瘤患者右室收缩压升高的发生率很高，这为增殖性造血干细胞与肺血管疾病密切相关提供了补充证据(5)。总之，这些研究指出了一种异常的造血祖/干细胞群体，这是PAH病理生理学的早期步骤。需要进一步的研究来确定造血祖/干细胞导致PAH的机制，以及这是否适用于该疾病的所有亚型。然而，针对干细胞的抗c-Kit药物伊马替尼对PAH有效，尽管并发症限制了它的使用。严及其同事(1)最近的工作(1)与先前的研究一起，为重新考虑以造血祖细胞/干细胞为靶点的治疗PAH的方法提供了强有力的理由。
We commend Yan and colleagues (1) on their elegant studies, which add to the accumulating evidence of a myeloid/bone marrow origin of pulmonary arterial hypertension (PAH). Using reciprocal bone marrow chimeras in immunocompetent Bmpr2 mutant and wild-type mouse models, the authors identify bone marrow-dependent mechanisms in the muscularization of pulmonary arterioles and right ventricular systolic pressure elevation, without right ventricular hypertrophy. The findings are complementary to our previous xenograft study (2), in which hematopoietic stem cells derived from patients with PAH were transplanted into immunocompromised mice. Similar to the work by Yan and colleagues (1), hematopoietic stem cells from patients had fivefold higher engraftment, and transplant of stem cells from patients with Bmpr2 mutations resulted in greater vascular smooth muscle cell hypertrophy than animals engrafted with mutation-negative PAH bone marrow stem cells. Just as important, prior study has shown that transplantation of serotonin 2B receptor-deficient bone marrow is protective against development of hypoxia-induced PAH (3), which indicates that myeloid stem cells can promote or block development of pulmonary vascular disease. Patients with PAH uniformly have an increase of hematopoietic progenitor and stem cell pools in the bone marrow compartment, even when there are no apparent blood abnormalities (2, 4). Intriguingly, patients with myeloproliferative malignancies, which are defined by clonal stem cell expansion, have a high incidence of elevated right ventricular systolic pressure, providing complementary evidence that proliferative hematopoietic stem cells are closely related to pulmonary vascular disease (5). Altogether, these studies point to an abnormal hematopoietic progenitor/stem cell population that is an early step in the pathophysiology of PAH. Future studies are needed to define mechanisms via which hematopoietic progenitor/stem cells lead to PAH and whether this holds true for all subgroups of the disease. However, the anti-c-Kit drug imatinib, which targets stem cells, was effective in PAH (6), although complications limited its use. The recent work by Yan and colleagues (1), together with prior studies, provides a strong rationale to reconsider approaches that target hematopoietic progenitor/stem cells in the treatment of PAH.■