scholarly journals Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

2018 ◽  
Vol 19 (9) ◽  
pp. 2534 ◽  
Author(s):  
Gareth Willis ◽  
Angeles Fernandez-Gonzalez ◽  
Monica Reis ◽  
S. Mitsialis ◽  
Stella Kourembanas
Keyword(s):  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Mesenchymal Stem Cell ◽  
Arterial Hypertension ◽  
Pulmonary Inflammation ◽  
Pulmonary Arteries ◽  
Cross Sectional ◽  
Macrophage Function ◽  
Beneficial Effects ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.

scholarly journals Beneficial effects of mesenchymal stem cell delivery via a novel cardiac bioscaffold on right ventricles of pulmonary arterial hypertensive rats

2019 ◽  
Vol 316 (5) ◽  
pp. H1005-H1013 ◽  
Author(s):  
Eric G. Schmuck ◽  
Timothy A. Hacker ◽  
David A. Schreier ◽  
Naomi C. Chesler ◽  
Zhijie Wang
Keyword(s):  
Quality Of Life ◽  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Mesenchymal Stem Cell ◽  
Arterial Hypertension ◽  
Stroke Work ◽  
Improve Quality ◽  
Beneficial Effects ◽  
Pulmonary Arterial

Right ventricular failure (RVF) is a common cause of death in patients suffering from pulmonary arterial hypertension (PAH). The current treatment for PAH only moderately improves symptoms, and RVF ultimately occurs. Therefore, it is necessary to develop new treatment strategies to protect against right ventricle (RV) maladaptation despite PAH progression. In this study, we hypothesize that local mesenchymal stem cell (MSC) delivery via a novel bioscaffold can improve RV function despite persistent PAH. To test our hypothesis, we induced PAH in adult rats with SU5416 and chronic hypoxia exposure; treated with rat MSCs delivered by intravenous injection, intramyocardial injection, or epicardial placement of a bioscaffold; and then examined treatment effectiveness by in vivo pressure-volume measurement, echocardiography, histology, and immunohistochemistry. Our results showed that compared with other treatment groups, only the MSC-seeded bioscaffold group resulted in RV functional improvement, including restored stroke volume, cardiac output, and improved stroke work. Diastolic function indicated by end-diastolic pressure-volume relationship was improved by the local MSC treatments or bioscaffold alone. Cardiomyocyte hypertrophy and RV fibrosis were both reduced, and von Willebrand factor expression was restored by the MSC-seeded bioscaffold treatment. Overall, our study suggests a potential new regenerative therapy to rescue the pressure-overload failing RV with persistent pulmonary vascular disease, which may improve quality of life and/or survival of PAH patients. NEW & NOTEWORTHY We explored the effects of mesenchymal stem cell-seeded bioscaffold on right ventricles (RVs) of rats with established pulmonary arterial hypertension (PAH). Some beneficial effects were observed despite persistent PAH, suggesting that this may be a new therapy for RV to improve quality of life and/or survival of PAH patients.

scholarly journals Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (17) ◽  
pp. 9105
Author(s):  
Malik Bisserier ◽  
Michael G. Katz ◽  
Carlos Bueno-Beti ◽  
Agnieszka Brojakowska ◽  
Shihong Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Pulmonary Arteries ◽  
Combination Therapies ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.

scholarly journals Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats

2014 ◽  
Vol 35 (9) ◽  
pp. 1121-1128 ◽  
Author(s):  
Jian-ying Chen ◽  
Ran An ◽  
Zhen-jun Liu ◽  
Jin-ju Wang ◽  
Shu-zhen Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Mesenchymal Stem Cell ◽  
Arterial Hypertension ◽  
Therapeutic Effects ◽  
Pulmonary Arterial

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

2018 ◽  
Vol 9 ◽  
Author(s):  
Allan K. N. Alencar ◽  
Pedro M. Pimentel-Coelho ◽  
Guilherme C. Montes ◽  
Marina de M. C. da Silva ◽  
Luiza V. P. Mendes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Mesenchymal Stem Cell ◽  
Cell Therapy ◽  
Arterial Hypertension ◽  
Stem Cell Therapy ◽  
Human Mesenchymal Stem Cell ◽  
Mesenchymal Stem Cell Therapy ◽  
Pulmonary Arterial

Abstract 14573: Association of Human Mesenchymal Stem Cell and Lodenafil in Hypoxia-induced Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Grazielle F Silva ◽  
Marina Silva ◽  
Jaqueline S Da Silva ◽  
Allan K Alencar ◽  
Tadeu Montagnoli ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Mesenchymal Stem Cell ◽  
Arterial Hypertension ◽  
Wall Thickness ◽  
Vascular Dysfunction ◽  
Control Group ◽  
Human Umbilical Cord ◽  
Vegf Receptor ◽  
Pulmonary Arterial

Introduction: Right ventricle (RV) remodeling and vascular dysfunction are present in pulmonary arterial hypertension (PAH). Hypothesis: This work focuses on the benefits of the association of human umbilical cord mesenchymal stem cell (hMSC) with lodenafil, a PDE5 inhibitor, on PAH in rats. Methods: Experiments were in accordance with the Animal Care and Use Committee at the Federal University of Rio de Janeiro. PAH was induced in male Wistar rats by exposure to hypoxia (10% O 2 ) during 3 weeks plus i.p . injection of an antagonist of VEGF receptor (SU5416; 20 mg/kg/week). Animals were randomly divided (n=6): PAH + vehicle; PAH + lodenafil (gavage, 10 mg/kg); PAH + lodenafil + hMSC (5x10 5 , i.v.) for 14 days. Results: PAH induced the reduction of the ratio of pulmonary acceleration time and RV ejection time from 0.42 ± 0.01 to 0.24 ± 0.01, which was recovered to 0.31 ± 0.01 after treatment with lodenafil + hMSC. RV afterload confirmed by increased systolic pressure (mmHg) of 52.1 ± 8.8 (contro: 24.0 ± 3.1) was normalized to 29.6 ± 2.2 with association. Pulmonary arteries wall thickness (%) measured by immunohistochemistry for alpha-SMA was increased by HAP from 44.7 ± 1.4 to 64.2 ± 1.2 and was partial (57.7 ± 1.4) or totally recovered (47.3 ± 0.9) after treatment with lodenafil and association, respectively. Increased RV collagen fraction (%) of 7.4 ± 1.2 was induced by HAP when compared to control group (1.9 ± 0.1) and although lodenafil did not alter this parameter (6.6 ± 0.9) its association with hMSC restored to 2.7 ± 0.4. Increased RV wall thickness (mm) observed in PAH (from 0.60 ± 0.02 to 1.05 ± 0.13) recovered to 0.58 ± 0.04 after treatment with association. ERK1/2 expression evaluated by western blot analysis recovered from 0.79 ± 0.07 to 0.12 ± 0.06, which reinforced the reduction of cellular proliferation by treatment with lodenafil + hMSC. RV expression of p38 mitogen associated protein kinase was measured by stained area quantification using immunohistochemistry (%) was also increased in PAH group (from 9.4 ± 2.5 to 31.4 ± 2.2, p < 0.05) and the association of lodenafil + hMSC reduced to 11.4 ± 3.4. Conclusions: Therapy of hMSC and lodenafil improved cardiac remodeling and vascular dysfunction in SuHx-PAH rats, representing an important approach for the future treatment of PAH.

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