Resident PW1+ Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
Resident PW1+ Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
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DOI：
10.1161/circresaha.115.307035
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发表时间：
2016-03-04
影响因子：
20.1
通讯作者：
Nadaud, Sophie
中科院分区：
文献类型：
--
作者：
Dierick, France;Hery, Tiphaine;Nadaud, Sophie
理由：肺动脉高压以血管重构和新生肌肉为特征。PW1（+）祖细胞在体外可分化为平滑肌细胞（SMCs）。目的：探讨PW1（+）祖细胞在肺动脉高压血管重构中的作用。方法和结果：我们研究了它们在Pw1（+）细胞和Pw1（+）细胞衍生的分化细胞中表达β -半乳糖苷酶的Pw1（nLacZ+/-）小鼠慢性缺氧诱导的血管重构中的作用。PW1（+）祖细胞存在于啮齿动物和人类对照肺的血管周围区。利用祖细胞标记，从小鼠肺中分离出3个不同的肌源性PW1（+）细胞群，其中2个在慢性缺氧4天后显著增加。肺PW1（+）细胞增殖数量和β -gal（+）血管SMC比例增加，表明在早期慢性缺氧诱导的新生肌肉形成过程中，PW1（+）细胞募集并向血管SMC分化。AMD3100抑制CXCR4可阻止PW1（+）细胞向SMC分化，但不抑制其增殖。骨髓移植实验表明，新形成的β -gal(+) SMC不是来自循环骨髓来源的PW1（+）祖细胞，证实了招募的PW1（+）细胞的常驻来源。大鼠肺PW1（+）细胞数量明显增加。在肺动脉高压患者的肺中，在重建的血管结构中观察到大量表达pw1的细胞。结论：这些结果表明存在一种新的常住SMC祖细胞群，表达PW1并参与肺动脉高压相关的血管重塑。
Rationale:Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1(+) progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro.Objective:To determine the role of pulmonary PW1(+) progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension.Methods and Results:We investigated their contribution during chronic hypoxia-induced vascular remodeling in Pw1(nLacZ+/-) mouse expressing beta-galactosidase in PW1(+) cells and in differentiated cells derived from PW1(+) cells. PW1(+) progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1(+) cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1(+) cells and the proportion of beta-gal(+) vascular SMC were increased, indicating a recruitment of PW1(+) cells and their differentiation into vascular SMC during early chronic hypoxia-induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1(+) cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed beta-gal(+) SMC were not derived from circulating bone marrow-derived PW1(+) progenitor cells, confirming a resident origin of the recruited PW1(+) cells. The number of pulmonary PW1(+) cells was also increased in rats after monocrotaline injection. In lung from pulmonary arterial hypertension patients, PW1-expressing cells were observed in large numbers in remodeled vascular structures.Conclusions:These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in pulmonary hypertension-associated vascular remodeling.