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Sun S, Mao J, Ding Y, Liu L, Gong J, Yang S, Li J, Kuang T, Miao R, Yang Y. Hypoxia Combined With Interleukin-17 Regulates Hypoxia-Inducible Factor-1α/Endothelial Nitric Oxide Synthase Expression in Pulmonary Artery Endothelial Cells. J Cell Mol Med 2025; 29:e70289. [PMID: 39823269 PMCID: PMC11740980 DOI: 10.1111/jcmm.70289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 11/26/2024] [Accepted: 12/04/2024] [Indexed: 01/19/2025] Open
Abstract
The pathogenesis of chronic thromboembolic pulmonary hypertension may be multifactorial and requires further studies. We explored alterations in pulmonary artery endothelial cells under the hypoxic and elevated interleukin-17 conditions that are commonly present in patients with chronic thromboembolic pulmonary hypertension. We measured the serum interleukin-17 levels in 10 chronic thromboembolic pulmonary hypertension patients and 10 healthy control persons. The expressions and localisations of hypoxia-inducible factor-1α and endothelial nitric oxide synthase were detected in tissues. The levels of hypoxia-inducible factor-1α, endothelial nitric oxide synthase, nitric oxide, and reactive oxygen species in cultured pulmonary artery endothelial cells were examined under hypoxia and/or interleukin-17 treatment. The serum interleukin-17 level was increased in chronic thromboembolic pulmonary hypertension patients. Hypoxia-inducible factor-1α was increased, and endothelial nitric oxide synthase was decreased in chronic thromboembolic pulmonary hypertension pulmonary vascular tissue. After receiving the hypoxia combined with interleukin-17 treatment, pulmonary artery endothelial cells showed increased levels of hypoxia-inducible factor-1α and phospho-endothelial nitric oxide synthase (Thr495) (p = 0.001 and 0.063, respectively) and a decreased level of endothelial nitric oxide synthase (p < 0.001). In addition, the nitric oxide level was significantly decreased (p = 0.001), whereas the reactive oxygen species level was insignificantly increased in pulmonary artery endothelial cells. Chronic thromboembolic pulmonary hypertension patients might experience increased inflammation and hypoxia due to dysregulation of the hypoxia-inducible factor-1α/endothelial nitric synthase pathway in pulmonary artery endothelial cells under inflammation and hypoxia, contributing to the pathogenesis of chronic thromboembolic pulmonary hypertension.
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Affiliation(s)
- Shuai Sun
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Jianjun Mao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Yuan Ding
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Lin Liu
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Juanni Gong
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Suqiao Yang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Jifeng Li
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Tuguang Kuang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Ran Miao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Yuanhua Yang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
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Hu X, Liu J, Song X, Yuan P. Stem cells in pulmonary hypertension: Current understanding and future challenges. Animal Model Exp Med 2024; 7:961-963. [PMID: 39439226 DOI: 10.1002/ame2.12482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 07/23/2024] [Indexed: 10/25/2024] Open
Abstract
Stem cells possess the unique ability to develop into different cell types within the body. Researchers are exploring the use of different types of stem cells to potentially repair damaged blood vessels, reduce inflammation, and improve overall vascular function, all of which are crucial factors in pulmonary hypertension (PH). While it is important to acknowledge that further clinical studies and trials are necessary to fully understand the efficacy and safety of stem cell therapy for PH, ongoing research and initial findings present promising avenues for potentially developing new treatments or therapeutic strategies for PH.
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Affiliation(s)
- Xiaoyi Hu
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinming Liu
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiao Song
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ping Yuan
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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Zheng R, Xu T, Wang X, Yang L, Wang J, Huang X. Stem cell therapy in pulmonary hypertension: current practice and future opportunities. Eur Respir Rev 2023; 32:230112. [PMID: 37758272 PMCID: PMC10523152 DOI: 10.1183/16000617.0112-2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/13/2023] [Indexed: 09/30/2023] Open
Abstract
Pulmonary hypertension (PH) is a progressive disease characterised by elevated pulmonary arterial pressure and right-sided heart failure. While conventional drug therapies, including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors, have been shown to improve the haemodynamic abnormalities of patients with PH, the 5-year mortality rate remains high. Thus, novel therapies are urgently required to prolong the survival of patients with PH. Stem cell therapies, including mesenchymal stem cells, endothelial progenitor cells and induced pluripotent stem cells, have shown therapeutic potential for the treatment of PH and clinical trials on stem cell therapies for PH are ongoing. This review aims to present the latest preclinical achievements of stem cell therapies, focusing on the therapeutic effects of clinical trials and discussing the challenges and future perspectives of large-scale applications.
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Affiliation(s)
- Ruixuan Zheng
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- These authors contributed equally to this work
| | - Tingting Xu
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- These authors contributed equally to this work
| | - Xinghong Wang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lehe Yang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Liu H, Liu J, Liu C, Niu X, Liu J. Transplantation of endothelial progenitor cells improves myocardial hypertrophy in spontaneously hypertensive rats through HO-1/CREB3/AKT axis. Arch Biochem Biophys 2023; 746:109739. [PMID: 37678424 DOI: 10.1016/j.abb.2023.109739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/31/2023] [Accepted: 09/04/2023] [Indexed: 09/09/2023]
Abstract
Hypertensive myocardial hypertrophy produces a hostile microenvironment characterized by cardiomyocyte hypertrophy, inflammation and oxidative stress, which also leads to endothelial progenitor cells (EPCs) dysfunction, preventing EPC migration, adhesion and angiogenesis. Heme oxygenase-1 (HO-1) is an intracellular protein that plays an important role in angiogenesis and cell survival. The upregulation of cAMP response element-binding protein 3 (CREB3) is closely related to the formation of endothelial cells. The purpose of this study was to evaluate the role of HO-1 and CREB3 in EPCs and their effects on hypertensive myocardial hypertrophy. EPCs were transfected with HO-1 adenoviral overexpression vector (Ad-HO-1) or together with CREB3 siRNA (si-CREB3), or transfected with CREB3 adenoviral overexpression vector (Ad-CREB3) or together with HO-1 siRNA, and then treated with 100 nM Ang Ⅱ for 12 h. Overexpressing HO-1 or CREB3 promoted adhesion to extracellular matrix, cell migration, and angiogenesis, inhibited the secretion of inflammatory factors TNF-α and IL-6, and reduced ROS level, ICAM-1 and MCP-1 mRNA expression levels in EPCs treated with Ang Ⅱ. Online prediction and Co-IP assay showed that HO-1 interacts with CREB3, and they promote expression of each other. EPC-conditioned medium supplemented with CREB3 recombinant protein decreased the levels of ANP and BNP mRNA in H9C2 cells treated with Ang Ⅱ and alleviated oxidative stress. Ad-CREB3 transfected EPCs promoted the phosphorylation of AKT in vivo and in vitro, thereby improving myocardial swelling and dysfunction in SHR rats. Taken together, transplantation of CREB3 overexpressing EPCs alleviates myocardial hypertrophy in spontaneously hypertensive rats by promoting HO-1 protein expression and AKT phosphorylation.
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Affiliation(s)
- Hui Liu
- Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Jing Liu
- Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Cong Liu
- Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Xiaolin Niu
- Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
| | - Jun Liu
- Military Personnel Medical Care Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
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Orieux A, Samson C, Pieroni L, Drouin S, Dang Van S, Migeon T, Frere P, Brunet D, Buob D, Hadchouel J, Guihaire J, Mercier O, Galichon P. Pulmonary hypertension without heart failure causes cardiorenal syndrome in a porcine model. Sci Rep 2023; 13:9130. [PMID: 37277538 PMCID: PMC10241877 DOI: 10.1038/s41598-023-36124-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/30/2023] [Indexed: 06/07/2023] Open
Abstract
Cardiorenal syndromes type 1 and 2 are complex disorders in which cardiac dysfunction leads to kidney dysfunction. However, the mechanisms remain incompletely explained, during pulmonary hypertension in particular. The objective of this study is to develop an original preclinical model of cardiorenal syndrome secondary to a pulmonary hypertension in piglets. Twelve 2-month-old Large White piglets were randomized in two groups: (1) induction of pulmonary hypertension by ligation of the left pulmonary artery and iterative embolizations of the right lower pulmonary artery, or (2) Sham interventions. We evaluated the cardiac function using right heart catheterization, echocardiography and measurement of biochemistry markers). Kidney was characterized using laboratory blood and urine tests, histological evaluation, immunostainings for renal damage and repair, and a longitudinal weekly assessment of the glomerular filtration rate using creatinine-based estimation and intravenous injection of an exogenous tracer on one piglet. At the end of the protocol (6 weeks), the mean pulmonary artery pressure (32 ± 10 vs. 13 ± 2 mmHg; p = 0.001), pulmonary vascular resistance (9.3 ± 4.7 vs. 2.5 ± 0.4 WU; p = 0.004) and central venous pressure were significantly higher in the pulmonary hypertension group while the cardiac index was not different. Piglets with pulmonary hypertension had higher troponin I. We found significant tubular damage and an increase in albuminuria in the pulmonary hypertension group and negative correlation between pulmonary hypertension and renal function. We report here the first porcine model of cardiorenal syndrome secondary to pulmonary hypertension.
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Affiliation(s)
- Arthur Orieux
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
| | - Chloé Samson
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
| | - Laurence Pieroni
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
- AP-HP Hôpital Tenon - Service de Biochimie, Paris, France
| | - Sarah Drouin
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
- Service Médico Chirurgical de Transplantation Rénale, AP-HP Hôpital Pitié Salpêtrière, Paris, France
| | - Simon Dang Van
- INSERM UMR_S999, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
- Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Service de Chirurgie Thoracique et Transplantation Cardio-Thoracique, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
| | - Tiffany Migeon
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
| | - Perrine Frere
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
| | - Dorothée Brunet
- INSERM UMR_S999, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
- Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Service de Chirurgie Thoracique et Transplantation Cardio-Thoracique, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
| | - David Buob
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
- AP-HP Hôpital Tenon - Service d'Anatomie Pathologique, Paris, France
| | - Juliette Hadchouel
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France
- Sorbonne Université, Paris, France
| | - Julien Guihaire
- INSERM UMR_S999, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
- Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Service de Chirurgie Thoracique et Transplantation Cardio-Thoracique, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
| | - Olaf Mercier
- INSERM UMR_S999, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
- Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Service de Chirurgie Thoracique et Transplantation Cardio-Thoracique, Hôpital Marie Lannelongue - Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France
| | - Pierre Galichon
- INSERM UMR_S1155 Bâtiment Recherche, CoRaKiD, Hôpital Tenon, 4 Rue de La Chine, 75020, Paris, France.
- Sorbonne Université, Paris, France.
- Service Médico Chirurgical de Transplantation Rénale, AP-HP Hôpital Pitié Salpêtrière, Paris, France.
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Transplantation of Endothelial Progenitor Cells: Summary and prospect. Acta Histochem 2023; 125:151990. [PMID: 36587456 DOI: 10.1016/j.acthis.2022.151990] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/17/2022] [Accepted: 12/18/2022] [Indexed: 12/31/2022]
Abstract
Endothelial Progenitor Cells (EPCs) are precursor cells of endothelial cells (ECs), which can differentiate into vascular ECs, protect from endothelial dysfunction and tissue ischemia, and reduce vascular hyperplasia. Due to these functions, EPCs are used as a candidate cell source for transplantation strategies. In recent years, a great progress was achieved in EPCs biology research, and EPCs transplantation has become a research hotspot. At present, transplanted EPCs have been used to treat ischemic diseases due to their powerful vasculogenesis and beneficial paracrine effects. Although EPCs transplantation has been proved to play an important role, the clinical application of EPCs still faces many challenges. This review briefly summarized the basic characteristics of EPCs, the process of EPCs transplantation promoting the healing of ischemic tissue, and the ways to improve the efficiency of EPCs transplantation. In addition, the application of EPCs in neurological improvement, cardiovascular and respiratory diseases and the challenges and problems in clinical application of EPCs were also discussed. In the end, the application of EPCs transplantation in regenerative medicine and tissue engineering was discussed.
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Smadja DM. Stem Cell Therapy, Artificial Heart or Xenotransplantation: What will be New “Regenerative” Strategies in Heart Failure during the Next Decade? Stem Cell Rev Rep 2022; 19:694-699. [PMID: 36383298 DOI: 10.1007/s12015-022-10476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2022] [Indexed: 11/17/2022]
Abstract
The main limitation of allotransplantation and in particular heart transplantation is the insufficient supply of donor organs. As alternative strategies to heart transplantation, stem cells opened the way of regenerative medicine in early 2000. While new biotechnologies tried to minimize side effects due to hemocompatibility in artificial hearts, progress in xenotransplantation allowed in 2022 to realize the first pig-to-human heart transplant on a compassionate use basis. This xenotransplantation has been successful thanks to genetically modified pigs using the CRISPR-Cas9 technology. Indeed, gene editing allowed modifications of immune responses and thrombotic potential to modulate graft and systemic reaction. Academic research and preclinical studies of xenogeneic tissues already used in clinic such as bioprosthesis valve and of new xenotransplantation options will be necessary to evaluate immune-thrombosis and organ/vascular damages more deeply to make this hope of xenotransplantation a clinical reality. Stem cells, artificial heart and xenotransplantation are all in line to overcome the lack of donor hearts. Combination of stem cell approaches and/or xenogeneic tissue and/or artificial organs are probably part of the research objectives to make these projects real in the short term.
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Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed, but potentially curable pulmonary vascular disease. The increased pulmonary vascular resistance in CTEPH is caused by unresolved proximal thrombus and secondary microvasculopathy in the pulmonary vasculature, leading to adaptive and maladaptive remodeling of the right ventricle (RV), eventual right heart failure, and death. Knowledge on the RV remodeling process in CTEPH is limited. The progression to RV failure in CTEPH is a markedly slower process. A detailed understanding of the pathophysiology and underlying mechanisms of RV remodeling may facilitate early diagnosis and the development of targeted therapy. While ultrasound, magnetic resonance imaging, right heart catheterization, and serum biomarkers have been used to assess cardiac function, the current treatment strategies reduce the afterload of the right heart, but are less effective in improving the maladaptive remodeling of the right heart. This review systematically summarizes the current knowledge on adaptive and maladaptive remodeling of the right heart in CTEPH from molecular mechanisms to clinical practice.
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Razazian M, Khosravi M, Bahiraii S, Uzan G, Shamdani S, Naserian S. Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells. World J Stem Cells 2021; 13:971-984. [PMID: 34567420 PMCID: PMC8422932 DOI: 10.4252/wjsc.v13.i8.971] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders. Although both cell populations have been already studied and used for their regenerative potentials, recently their special immunoregulatory features have brought much more attention. Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response, particularly T cell proliferation, activation, and cytokine production. This makes them suitable choices for allogeneic stem cell transplantation. Nevertheless, these two cells do not have equal immunoregulatory activities. Many elements including their extraction sources, age/passage, expression of different markers, secretion of bioactive mediators, and some others could change the efficiency of their immunosuppressive function. However, to our knowledge, no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells. This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression, deactivation, cytokine production, and regulatory T cells induction capacities. Moreover, it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.
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Affiliation(s)
- Mehdi Razazian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
| | - Maryam Khosravi
- Microenvironment & Immunity Unit, Institut Pasteur, Paris 75724, France
- Institut national de la santé et de la recherche médicale (Inserm) Unit 1224, Paris 75724, France
| | - Sheyda Bahiraii
- Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria
| | - Georges Uzan
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
| | - Sara Shamdani
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France
| | - Sina Naserian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France.
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Stam K, Clauss S, Taverne YJHJ, Merkus D. Chronic Thromboembolic Pulmonary Hypertension - What Have We Learned From Large Animal Models. Front Cardiovasc Med 2021; 8:574360. [PMID: 33937352 PMCID: PMC8085273 DOI: 10.3389/fcvm.2021.574360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
Chronic thrombo-embolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism. In CTEPH, pulmonary vascular resistance, which is initially elevated due to the obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodeling. The increased afterload of the right ventricle (RV) leads to RV dilation and hypertrophy. This RV remodeling predisposes to arrhythmogenesis and RV failure. Yet, mechanisms involved in pulmonary microvascular remodeling, processes underlying the RV structural and functional adaptability in CTEPH as well as determinants of the susceptibility to arrhythmias such as atrial fibrillation in the context of CTEPH remain incompletely understood. Several large animal models with critical clinical features of human CTEPH and subsequent RV remodeling have relatively recently been developed in swine, sheep, and dogs. In this review we will discuss the current knowledge on the processes underlying development and progression of CTEPH, and on how animal models can help enlarge understanding of these processes.
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Affiliation(s)
- Kelly Stam
- Department of Cardiology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Sebastian Clauss
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University Munich, Munich, Germany.,Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Yannick J H J Taverne
- Department of Cardiothoracic Surgery, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Daphne Merkus
- Department of Cardiology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.,Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich, Munich Heart Alliance, Munich, Germany
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11
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Nouri Barkestani M, Shamdani S, Afshar Bakshloo M, Arouche N, Bambai B, Uzan G, Naserian S. TNFα priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application. Cell Commun Signal 2021; 19:1. [PMID: 33397378 PMCID: PMC7784277 DOI: 10.1186/s12964-020-00683-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/10/2020] [Indexed: 12/20/2022] Open
Abstract
Background Bone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions. Methods EPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNFα priming would increase EPC immunosuppressive and immunomodulatory effect. Results Treating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNFα treatment led to the TNFα-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions. Conclusions We report for the first time the crucial impact of inflammation notably the TNFα-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNFα-TNFR1 axis and, inversely the anti-inflammatory implication of the TNFα-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNFα prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs’ longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration.
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