Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

Abstract

Aims: Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH.Methods and Results: C57BL/6 mice (20–25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly s.c. injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 105 hMSCs cells suspended in 50 μL of vehicle (0.6 U/mL DNaseI in PBS) through intravenous injection in the caudal vein. PAH mice were treated only with vehicle. Ratio between pulmonary artery acceleration time and RV ejection time (PAAT/RVET), measure by echocardiography, was significantly reduced in the PAH mice, compared with controls, and therapy with hMSCs normalized this. Significant muscularization of the PA was observed in the PAH mice and hMSC reduced the number of fully muscularized vessels. RV free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy. Levels of markers of exacerbated apoptosis, tissue inflammation and damage, cell proliferation and oxidative stress were significantly greater in both lungs and RV tissues from PAH group, compared to controls. hMSC injection in PAH animals normalized the expression of these molecules which are involved with PAH and RV dysfunction development and the state of chronicity.Conclusion: These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.

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

“…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].…”

Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways

“…EVs have been recognized as important messengers for cell-to-cell communication via transfer of the various factors contained therein [1,2,3,4]. Recent studies have shown that the therapeutic efficacy of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) in various disorders, such as cardiovascular diseases [5], lung injury [6,7,8], acute kidney injury [9], fetal hypoxic ischemic brain injury [10], skin wound healing [11], and hypoxic pulmonary hypertension [12], is largely mediated by the transfer of mRNAs, miRNAs, and proteins via MSC-derived EVs [6,8,13,14,15,16]. The major advantage of using cell-free MSC-derived EV therapy over transplantation of live MSCs is that EVs can overcome the concerns associated with live cell therapy.…”

Carbenoxolone decreases monocrotaline‑induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes

“…A change in the shape of the pulmonary artery outflow waveform in combination with PAAT have been demonstrated to be a good echocardiographic indicator of PH (36); therefore, doppler echocardiography was used to confirm the establishment of MCT-induced PH (Fig. 1A and B).…”