Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension.
Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension.
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DOI：
10.1002/stem.548
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发表时间：
2011-01
期刊：
影响因子：
5.2
通讯作者：
Kourembanas, Stella
中科院分区：
文献类型：
--
作者：
Liang, Olin D.;Mitsialis, S. Alex;Chang, Mun Seog;Vergadi, Eleni;Lee, Changjin;Aslam, Muhammad;Fernandez-Gonzalez, Angeles;Liu, Xianlan;Baveja, Rajiv;Kourembanas, Stella
肺动脉高压（PAH）仍然是一种严重的疾病，虽然目前的治疗方法可以延长和改善生活质量，但寻找新的有效治疗方法是有必要的。使用转基因小鼠系，我们测试了骨髓来源的基质细胞（MSCs）治疗慢性缺氧诱导的多环芳烃的能力。受体小鼠暴露于常压缺氧（8%-10% O2） 5周，通过颈静脉注射MSC制剂，并在再缺氧2周后评估其对PAH的影响。来自野生型（WT）小鼠或血红素加氧酶-1 （HO-1）缺失小鼠（Hmox1KO）的供体间充质干细胞在移植到WT或Hmox1KO受体时，对PAH具有部分保护作用，而从含有人类HO-1转基因的转基因小鼠分离的间充质干细胞在表面活性剂蛋白C启动子（SHO1系）的控制下治疗，可以逆转WT受体的既定疾病。SH01-MSC治疗Hmox1KO动物在长时间缺氧条件下发生右心室梗死，使右心室收缩压正常，右心室肥厚明显减轻，预防右心室梗死。从多西环素诱导的双基因小鼠系中分离的供体间充质干细胞，肺特异性表达HO-1，仅在多西环素治疗受体后才显示出类似的治疗效果。体外实验表明，MSC作用的潜在机制包括调节缺氧诱导的肺部炎症和抑制平滑肌细胞增殖。总的来说，我们的研究结果表明MSCs改善了慢性缺氧诱导的PAH，并且移植细胞中肺特异性HO-1的表达高度增强了其功效，表明HO-1依赖性和HO-1非依赖性保护途径之间存在相互作用。
Pulmonary arterial hypertension (PAH) remains a serious disease, and, while current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically-modified mouse lines, we tested the ability of bone marrow-derived stromal cells (MSCs), to treat chronic hypoxia-induced PAH. Recipient mice were exposed for five weeks to normobaric hypoxia (8%–10% O2), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or Heme Oxygenase-1 (HO-1) null mice (Hmox1KO) conferred partial protection from PAH when transplanted into WT or Hmox1KO recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SHO1 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1KO animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only upon doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulative, our results demonstrate that MSCs ameliorate chronic hypoxia – induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1 dependent and HO-1 independent protective pathways.
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DOI：
10.1164/rccm.200902-0242oc
发表时间：
2009-12-01
影响因子：
24.7
作者：
Aslam, Muhammad;Baveja, Rajiv;Kourembanas, Stella
通讯作者：
Kourembanas, Stella
DOI：
10.1152/ajpheart.00937.2004
发表时间：
2005-06-01
影响因子：
4.8
作者：
Christou, H;Bailey, N;Kourembanas, S
通讯作者：
Kourembanas, S
DOI：
10.1073/pnas.161272598
发表时间：
2001-07-17
影响因子：
11.1
作者：
Minamino, T;Christou, H;Kourembanas, S
通讯作者：
Kourembanas, S
DOI：
10.1073/pnas.1432929100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Ortiz, LA;Gambelli, F;Phinney, DG
通讯作者：
Phinney, DG
DOI：
10.1073/pnas.0704421104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Ortiz, Luis A.;DuTreil, Maria;Phinney, Donald G.
通讯作者：
Phinney, Donald G.