Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension

被引：55

作者：

de Mendonca, Lucas ^{[1
,2
]}

Felix, Nathane S. ^{[1
,2
]}

Blanco, Natalia G. ^{[1
,2
]}

Da Silva, Jaqueline S. ^{[3
]}

Ferreira, Tatiana P. ^{[5
]}

Abreu, Soraia C. ^{[1
,2
]}

Cruz, Fernanda F. ^{[1
,2
]}

Rocha, Nazareth ^{[1
,4
]}

Silva, Patricia M. ^{[5
]}

Martins, Vanessa ^{[1
,6
]}

Capelozzi, Vera L. ^{[6
]}

Zapata-Sudo, Gizele ^{[3
]}

Rocco, Patricia R. M. ^{[1
,2
]}

Silva, Pedro L. ^{[1
,2
]}

机构：

[1] Univ Fed Rio de Janeiro, Lab Pulm Invest, Carlos Chagas Filho Biophys Inst, Ctr Ciencias Saude, Ave Carlos Chagas Filho S-N,Bloco G-014, BR-21941902 Rio De Janeiro, RJ, Brazil

[2] Natl Inst Sci & Technol Regenerat Med, Rio De Janeiro, RJ, Brazil

[3] Univ Fed Rio de Janeiro, Lab Cardiovasc Pharmacol, Rio De Janeiro, RJ, Brazil

[4] Fluminense Fed Univ, Dept Physiol, Niteroi, RJ, Brazil

[5] Fundacao Oswaldo Cruz, Lab Inflammat, Oswaldo Cruz Inst, Rio De Janeiro, RJ, Brazil

[6] Univ Sao Paulo, Lab Histomorphometry & Lung Genom, Fac Med, Sao Paulo, SP, Brazil

来源：

STEM CELL RESEARCH & THERAPY | 2017年 / 8卷

关键词：

Pulmonary arterial hypertension; Mesenchymal stromal cells; Hemodynamics; Lung vascular remodeling; Macrophage phenotype; ENDOTHELIAL GROWTH-FACTOR; STEM-CELL; PLEXIFORM LESIONS; NONINVASIVE ASSESSMENT; REGENERATIVE CELL; PROGENITOR CELLS; ANIMAL-MODELS; BONE-MARROW; MONOCROTALINE; APOPTOSIS;

D O I：

10.1186/s13287-017-0669-0

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Background: Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Methods: Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial-mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68(+) and CD163(+) macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. Results: In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 +/- 1 vs 39 +/- 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68(+) macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial-mesenchymal transition. Conclusion: In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype.

引用

页数：15

共 72 条

[11] Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction [J].