Asosingh Kewal, Wanner Nicholas, Weiss Kelly, Queisser Kimberly, Gebreab Liya, Kassa Biruk, Stuehr Eric, Graham Brian, Erzurum Serpil
Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH.
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO; and.
Blood Adv. 2017 Mar 17;1(9):526-534. doi: 10.1182/bloodadvances.2016002691. eCollection 2017 Mar 28.
Accumulating evidence shows a causative role for the bone marrow (BM) in the genesis and progression of pulmonary hypertension (PH). Engraftment of BM hematopoietic stem cells from PH patients to mice reproduces the cardiopulmonary pathology of PH. However, it is unknown whether healthy BM can prevent the development of right heart disease. -deficient ( KO) mice develop cardiopulmonary disease with manifestations resembling PH, including elevated right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary endothelial proliferative disease. Here, we hypothesize that engraftment of healthy BM to KO mice will prevent pulmonary vascular remodeling and development of the cardiopulmonary disease. KO mice and wild-type (WT) mice underwent transplantation with WT or KO BM. Hematopoietic differentiation was analyzed by flow cytometry. Pulmonary endothelial remodeling was quantified by CD31 image analysis. RVSP and RV cardiomyocyte area or Fulton's index were used to analyze RV hypertrophy. Maladaptive RV hypertrophy was determined by quantification of RV fibrosis. Transplantation of KO BM into healthy recipient WT mice led to elevation of RVSP, RV hypertrophy, and pulmonary endothelial remodeling. Reconstitution of KO with WT BM prevented spontaneous development of PH, including elevation of RVSP and maladaptive RV hypertrophy, but not pulmonary endothelial remodeling. Healthy BM has a protective role in the right ventricle independent of pulmonary vascular disease.
越来越多的证据表明，骨髓（BM）在肺动脉高压（PH）的发生和发展中起因果作用。将PH患者的骨髓造血干细胞移植到小鼠体内可重现PH的心肺病理变化。然而，健康的骨髓是否能预防右心疾病的发展尚不清楚。-缺陷（KO）小鼠会发展出类似于PH的心肺疾病，包括右心室（RV）收缩压（RVSP）升高、RV肥大和肺内皮增殖性疾病。在此，我们假设将健康的骨髓移植到KO小鼠体内将预防肺血管重塑和心肺疾病的发展。对KO小鼠和野生型（WT）小鼠进行WT或KO骨髓移植。通过流式细胞术分析造血分化。通过CD31图像分析对肺内皮重塑进行定量。使用RVSP和RV心肌细胞面积或富尔顿指数分析RV肥大。通过定量RV纤维化来确定适应性不良的RV肥大。将KO骨髓移植到健康的受体WT小鼠体内会导致RVSP升高、RV肥大和肺内皮重塑。用WT骨髓重建KO可预防PH的自发发展，包括RVSP升高和适应性不良的RV肥大，但不能预防肺内皮重塑。健康的骨髓在右心室中具有独立于肺血管疾病的保护作用。
