Transplantation of mesenchymal stem cells attenuates pulmonary hypertension by normalizing the endothelial-to-mesenchymal transition

Junyi Huang, Wenju Lu, Haiping Ouyang, Yuqin Chen, Chenting Zhang, Xiaoyun Luo, Meichan Li, Jiaze Shu, Qiuyu Zheng, Haixia Chen, Jiyuan Chen, Haiyang Tang, Dejun Sun, Jason X.J. Yuan, Kai Yang, Jian Wang

Research output: Contribution to journalArticle

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Abstract

For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP1 MSCs were traced at different time points in the lung tissue of a chronic hypoxia–induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia–induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia–induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2a, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.

Original languageEnglish (US)
Pages (from-to)49-60
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Mesenchymal Stem Cell Transplantation
Stem cells
Mesenchymal Stromal Cells
Pulmonary Hypertension
Lung
Endothelial cells
Endothelial Cells
Rats
CD31 Antigens
Vimentin
Conditioned Culture Medium
Cell- and Tissue-Based Therapy
Fibronectins
Proteolysis
Cell Movement
Arterial Pressure
Collagen
Stem Cells
Therapeutics
Inflammation

Keywords

  • Endothelial-to-mesenchymal transition
  • Mesenchymal stem cells
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Transplantation of mesenchymal stem cells attenuates pulmonary hypertension by normalizing the endothelial-to-mesenchymal transition. / Huang, Junyi; Lu, Wenju; Ouyang, Haiping; Chen, Yuqin; Zhang, Chenting; Luo, Xiaoyun; Li, Meichan; Shu, Jiaze; Zheng, Qiuyu; Chen, Haixia; Chen, Jiyuan; Tang, Haiyang; Sun, Dejun; Yuan, Jason X.J.; Yang, Kai; Wang, Jian.

In: American journal of respiratory cell and molecular biology, Vol. 62, No. 1, 01.01.2020, p. 49-60.

Research output: Contribution to journalArticle

Huang, J, Lu, W, Ouyang, H, Chen, Y, Zhang, C, Luo, X, Li, M, Shu, J, Zheng, Q, Chen, H, Chen, J, Tang, H, Sun, D, Yuan, JXJ, Yang, K & Wang, J 2020, 'Transplantation of mesenchymal stem cells attenuates pulmonary hypertension by normalizing the endothelial-to-mesenchymal transition', American journal of respiratory cell and molecular biology, vol. 62, no. 1, pp. 49-60. https://doi.org/10.1165/rcmb.2018-0165OC
Huang, Junyi ; Lu, Wenju ; Ouyang, Haiping ; Chen, Yuqin ; Zhang, Chenting ; Luo, Xiaoyun ; Li, Meichan ; Shu, Jiaze ; Zheng, Qiuyu ; Chen, Haixia ; Chen, Jiyuan ; Tang, Haiyang ; Sun, Dejun ; Yuan, Jason X.J. ; Yang, Kai ; Wang, Jian. / Transplantation of mesenchymal stem cells attenuates pulmonary hypertension by normalizing the endothelial-to-mesenchymal transition. In: American journal of respiratory cell and molecular biology. 2020 ; Vol. 62, No. 1. pp. 49-60.
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abstract = "For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP1 MSCs were traced at different time points in the lung tissue of a chronic hypoxia–induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia–induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia–induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2a, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.",
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AU - Huang, Junyi

AU - Lu, Wenju

AU - Ouyang, Haiping

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AU - Zhang, Chenting

AU - Luo, Xiaoyun

AU - Li, Meichan

AU - Shu, Jiaze

AU - Zheng, Qiuyu

AU - Chen, Haixia

AU - Chen, Jiyuan

AU - Tang, Haiyang

AU - Sun, Dejun

AU - Yuan, Jason X.J.

AU - Yang, Kai

AU - Wang, Jian

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N2 - For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP1 MSCs were traced at different time points in the lung tissue of a chronic hypoxia–induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia–induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia–induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2a, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.

AB - For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP1 MSCs were traced at different time points in the lung tissue of a chronic hypoxia–induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia–induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia–induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2a, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.

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