Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition

Huang, Junyi; Lu, Wenju; Ouyang, Huiyi; Chen, Yuqin; Zhang, Chenting; Luo, Xiaoning; Li, Meichan; Shu, Jiaze; Zheng, Qiuyu; Chen, Hạixia; Chen, Jiyuan; Tang, Haiyang; Sun, Dejun; Yuan, Jason X.‐J.; Yang, Kai

doi:10.1165/rcmb.2018-0165oc

Cited by 18 publications

(15 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the known benefits of stem cell transplantation for improvement of RV pressure, hypertrophy, and inflammation in animal models of PH, and even though EndMT has been reported as a feature of endothelial dysfunction in human PAH (147) and animal models of the disease [MCT (132,145) and Sugen-hypoxia (61)], only a few studies explored the potential for targeting PH-associated EndMT using stem cell therapies. Promising early evidence came from the recent work by Huang et al (76). The authors showed that intravenous injection of MSCs reduced RV systolic pressure, RV hypertrophy and pulmonary vascular muscularization, attenuated increases in collagen deposition, and normalized MMP2 and MMP9 tissue expression in Sugen-hypoxia rats.…”

Section: Endmt In Pah 903mentioning

confidence: 99%

Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Gorelova

Berman

Ghouleh

2021

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Endothelial-to-mesenchymal transition (EndMT) is a process that encompasses extensive transcriptional reprogramming of activated endothelial cells leading to a shift toward mesenchymal cellular phenotypes and functional responses. Initially observed in the context of embryonic development, in the last few decades EndMT is increasingly recognized as a process that contributes to a variety of pathologies in the adult organism. Within the settings of cardiovascular biology, EndMT plays a role in various diseases, including atherosclerosis, heart valvular disease, cardiac fibrosis, and myocardial infarction. EndMT is also being progressively implicated in development and progression of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). This review covers the current knowledge about EndMT in PH and PAH, and provides comprehensive overview of seminal discoveries. Topics covered include evidence linking EndMT to factors associated with PAH development, including hypoxia responses, inflammation, dysregulation of bone-morphogenetic protein receptor 2 (BMPR2), and redox signaling. This review amalgamates these discoveries into potential insights for the identification of underlying mechanisms driving EndMT in PH and PAH, and discusses future directions for EndMT-based therapeutic strategies in disease management. Antioxid. Redox Signal. 34, 891-914.

show abstract

Section: Endmt In Pah 903mentioning

confidence: 99%

Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Gorelova

Berman

Ghouleh

2021

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…Therefore, targeting KCNK3 might restore EC function; however, the mechanisms remain unknown [ 189 ]. The transplantation of mesenchymal cells in rats from the SuHx model improved haemodynamic parameters, but, more interestingly, reduced EndoMT (partially) through the modulation of HIF2α expression [ 190 ]. Furthermore, mesenchymal stem cells are also suggested to reduce inflammation through the secretion of paracrine factors and attenuate vascular remodeling by lowering collagen deposition [ 190 , 191 , 192 ].…”

Section: Current and Future Perspectivesmentioning

confidence: 99%

“…Furthermore, mesenchymal stem cells are also suggested to reduce inflammation through the secretion of paracrine factors and attenuate vascular remodeling by lowering collagen deposition [ 190 , 191 , 192 ]. However, the underlying mechanisms for this observation remain unclear [ 190 ]. Several recent studies demonstrate the role of endothelial HIF-2a in the pathogenesis of PAH, and therapeutic targeting of HIF-2a with small molecule inhibitors, such as PT2567, have showed a beneficial effect in PAH in vivo [ 193 , 194 ].…”

Section: Current and Future Perspectivesmentioning

confidence: 99%

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

et al. 2021

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.

show abstract

“…Pulmonary arterial hypertension (PAH) is a chronic and devastating disease in which extensive obliterative changes are associated with elevated pulmonary arteries pressure, pulmonary vascular resistance, and right ventricular (RV) dysfunction, resulting in vascular fibrosis and stiffening [108,109]. Mounting evidence has shown that treatment with rat MSC or human MSC treatment is able to decrease pulmonary vascular resistance, improve vascular endothelial function and right ventricular function in the monocrotaline or Su5416/hypoxia-injured lung [110][111][112][113] through regulating [Ca 2+ ]i signal-associated cellular behaviours [114], normalizing the expression levels of apoptosis (active-caspase-3), cellular proliferation (p-38 MAPK and ERK5), and inflammation markers (TNF-α, IL-1β, IL-6) [115], suppressing TLR-4 signalling [116], expressing Heme Oxygenase-1 (HO-1), enhancing let-7a expression [117], and dampening endothelialmesenchymal transition (EndMT) [118,119]. Moreover, high throughput sequencing has demonstrated that six miRNAs of MSCs (upregulated: miR573 and miR1246; downregulated: miR206, miR-133a-3p, miR-141-3p and miR-200a-3p) are differentially expressed with co-culturing with human pulmonary arterial endothelial cells (HPAECs) [120].…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

Guo

Deng

2020

Stem Cell Rev and Rep

View full text Add to dashboard Cite

Mesenchymal stromal cells (MSCs) as a kind of pluripotent adult stem cell have shown great therapeutic potential in relation to many diseases in anti-inflammation and regeneration. The results of preclinical experiments and clinical trials have demonstrated that MSC-derived secretome possesses immunoregulatory and reparative abilities and that this secretome is capable of modulating innate and adaptive immunity and reprograming the metabolism of recipient cells via paracrine mechanisms. It has been recognized that MSC-derived secretome, including soluble proteins (cytokines, chemokines, growth factors, proteases), extracellular vesicles (EVs) and organelles, plays a key role in tissue repair and regeneration in bronchopulmonary dysplasia, acute respiratory distress syndrome (ARDS), bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension, and silicosis. This review summarizes the known functions of MSC-EV modulation in lung diseases, coupled with the future challenges of MSC-EVs as a new pharmaceutical agent. The identification of underlying mechanisms for MSC-EV might provide a new direction for MSC-centered treatment in lung diseases.Graphical abstract

show abstract

Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition

Cited by 18 publications

References 25 publications

Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

Contact Info

Product

Resources

About