Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Stem Cell and Exosome Therapy in Pulmonary Hypertension

  • Seyeon Oh (Gachon Cardiovascular Research Institute, Gachon University) ;
  • Ji-Hye Jung (Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine) ;
  • Kyung-Jin Ahn (Gachon Cardiovascular Research Institute, Gachon University) ;
  • Albert Youngwoo Jang (Gachon Cardiovascular Research Institute, Gachon University) ;
  • Kyunghee Byun (Gachon Cardiovascular Research Institute, Gachon University) ;
  • Phillip C. Yang (Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine) ;
  • Wook-Jin Chung (Gachon Cardiovascular Research Institute, Gachon University)
  • Received : 2021.05.31
  • Accepted : 2021.12.13
  • Published : 2022.02.01
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Abstract

Pulmonary hypertension is a rare and progressive illness with a devastating prognosis. Promising research efforts have advanced the understanding and recognition of the pathobiology of pulmonary hypertension. Despite remarkable achievements in terms of improving the survival rate, reducing disease progression, and enhancing quality of life, pulmonary arterial hypertension (PAH) is not completely curable. Therefore, an effective treatment strategy is still needed. Recently, many studies of the underlying molecular mechanisms and technological developments have led to new approaches and paradigms for PAH treatment. Management based on stem cells and related paracrine effects, epigenetic drugs and gene therapies has yielded prospective results for PAH treatment in preclinical research. Further trials are ongoing to optimize these important insights into clinical circumstances.

Keywords

Acknowledgement

The figure was illustrated by Young-Jun Oh, who worked as a nurse at Gachon University Gil Medical Center.

References

  1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.
  2. Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med 2016;4:306-22. https://doi.org/10.1016/S2213-2600(15)00543-3
  3. Leber L, Beaudet A, Muller A. Epidemiology of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: identification of the most accurate estimates from a systematic literature review. Pulm Circ 2021;11:2045894020977300.
  4. Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019;53:1801887.
  5. Guignabert C, Tu L, Girerd B, et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 2015;147:529-37. https://doi.org/10.1378/chest.14-0862
  6. Frid MG, Thurman JM, Hansen KC, Maron BA, Stenmark KR. Inflammation, immunity, and vascular remodeling in pulmonary hypertension; evidence for complement involvement? Glob Cardiol Sci Pract 2020;2020:e202001.
  7. Yeo Y, Yi ES, Kim JM, et al. FGF12 (fibroblast growth factor 12) inhibits vascular smooth muscle cell remodeling in pulmonary arterial hypertension. Hypertension 2020;76:1778-86. https://doi.org/10.1161/HYPERTENSIONAHA.120.15068
  8. Ahn KJ, Jang AY, Park SJ, Chung WJ. 15 years journey of idiopathic pulmonary arterial hypertension with BMPR2 mutation. Clin Hypertens 2019;25:22.
  9. Jang AY, Kim BG, Kwon S, et al. Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: the PILGRIM explorative cohort. PLoS One 2020;15:e0238698.
  10. Lee H, Yeom A, Kim KC, Hong YM. Effect of ambrisentan therapy on the expression of endothelin receptor, endothelial nitric oxide synthase and NADPH oxidase 4 in monocrotaline-induced pulmonary arterial hypertension rat model. Korean Circ J 2019;49:866-76. https://doi.org/10.4070/kcj.2019.0006
  11. Jang AY, Kim S, Park SJ, et al. A nationwide multicenter registry and biobank program for deep phenotyping of idiopathic and hereditary pulmonary arterial hypertension in Korea: the PAH platform for deep phenotyping in Korean subjects (PHOENIKS) cohort. Clin Hypertens 2019;25:21.
  12. Sitbon O, Gomberg-Maitland M, Granton J, et al. Clinical trial design and new therapies for pulmonary arterial hypertension. Eur Respir J 2019;53:1801908.
  13. Berghausen EM, Feik L, Zierden M, Vantler M, Rosenkranz S. Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension. Herz 2019;44:130-7. https://doi.org/10.1007/s00059-019-4795-6
  14. Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006;168:659-69. https://doi.org/10.2353/ajpath.2006.050599
  15. Yu YA, Malakhau Y, Yu CA, et al. Nonclassical monocytes sense hypoxia, regulate pulmonary vascular remodeling, and promote pulmonary hypertension. J Immunol 2020;204:1474-85. https://doi.org/10.4049/jimmunol.1900239
  16. Fazal S, Bisserier M, Hadri L. Molecular and genetic profiling for precision medicines in pulmonary arterial hypertension. Cells 2021;10:638.
  17. Pu X, Du L, Hu Y, Fan Y, Xu Q. Stem/progenitor cells and pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2021;41:167-78. https://doi.org/10.1161/ATVBAHA.120.315052
  18. Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med 2019;4:22.
  19. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 2014;15:1009-16. https://doi.org/10.1038/ni.3002
  20. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. https://doi.org/10.1126/science.284.5411.143
  21. Mohsin S, Houser SR. Cortical bone derived stem cells for cardiac wound healing. Korean Circ J 2019;49:314-25. https://doi.org/10.4070/kcj.2018.0437
  22. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-7. https://doi.org/10.1080/14653240600855905
  23. Bui TV, Hwang JW, Lee JH, Park HJ, Ban K. Challenges and limitations of strategies to promote therapeutic potential of human mesenchymal stem cells for cell-based cardiac repair. Korean Circ J 2021;51:97-113. https://doi.org/10.4070/kcj.2020.0518
  24. Roobrouck VD, Ulloa-Montoya F, Verfaillie CM. Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res 2008;314:1937-44. https://doi.org/10.1016/j.yexcr.2008.03.006
  25. Jun D, Garat C, West J, et al. The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells 2011;29:725-35. https://doi.org/10.1002/stem.604
  26. Bordenave J, Tu L, Berrebeh N, et al. Lineage tracing reveals the dynamic contribution of pericytes to the blood vessel remodeling in pulmonary hypertension. Arterioscler Thromb Vasc Biol 2020;40:766-82. https://doi.org/10.1161/ATVBAHA.119.313715
  27. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-76. https://doi.org/10.1016/j.cell.2006.07.024
  28. Morita Y, Okura H, Matsuyama A. Patent application trends of induced pluripotent stem cell technologies in the United States, Japanese, and European applications. Biores Open Access 2019;8:45-58. https://doi.org/10.1089/biores.2018.0028
  29. Mandai M, Kurimoto Y, Takahashi M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 2017;377:792-3. https://doi.org/10.1056/NEJMc1706274
  30. Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I safety clinical trial. Chest 2017;151:971-81. https://doi.org/10.1016/j.chest.2016.10.061
  31. Braza F, Dirou S, Forest V, et al. Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells 2016;34:1836-45. https://doi.org/10.1002/stem.2344
  32. Oh S, Jang AY, Chae S, et al. Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension. Sci Rep 2021;11:2012.
  33. Huang WC, Ke MW, Cheng CC, et al. Therapeutic benefits of induced pluripotent stem cells in monocrotaline-induced pulmonary arterial hypertension. PLoS One 2016;11:e0142476.
  34. Gu M, Shao NY, Sa S, et al. Patient-specific iPSC-derived endothelial cells uncover pathways that protect against pulmonary hypertension in BMPR2 mutation carriers. Cell Stem Cell 2017;20:490-504.e5. https://doi.org/10.1016/j.stem.2016.08.019
  35. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020;367:eaau6977.
  36. van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a common pathway for a specialized function. J Biochem 2006;140:13-21. https://doi.org/10.1093/jb/mvj128
  37. Glembotski CC. Expanding the paracrine hypothesis of stem cell-mediated repair in the heart: when the unconventional becomes conventional. Circ Res 2017;120:772-4. https://doi.org/10.1161/CIRCRESAHA.116.310298
  38. Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res (Amst) 2007;1:129-37. https://doi.org/10.1016/j.scr.2008.02.002
  39. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res (Amst) 2010;4:214-22. https://doi.org/10.1016/j.scr.2009.12.003
  40. Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 2011;9:12.
  41. Wang K, Jiang Z, Webster KA, et al. Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal microRNA-21. Stem Cells Transl Med 2017;6:209-22. https://doi.org/10.5966/sctm.2015-0386
  42. Lee C, Mitsialis SA, Aslam M, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 2012;126:2601-11. https://doi.org/10.1161/CIRCULATIONAHA.112.114173
  43. Zhang S, Liu X, Ge LL, et al. Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling. Respir Res 2020;21:71.
  44. Sun F, Wang G, Pradhan A, et al. Nanoparticle delivery of STAT3 alleviates pulmonary hypertension in a mouse model of alveolar capillary dysplasia. Circulation 2021;144:539-55. https://doi.org/10.1161/CIRCULATIONAHA.121.053980
  45. Khan M, Nickoloff E, Abramova T, et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 2015;117:52-64. https://doi.org/10.1161/CIRCRESAHA.117.305990
  46. Wang Y, Zhang L, Li Y, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 2015;192:61-9. https://doi.org/10.1016/j.ijcard.2015.05.020
  47. Jung JH, Fu X, Yang PC. Exosomes generated from iPSC-derivatives: new direction for stem cell therapy in human heart diseases. Circ Res 2017;120:407-17. https://doi.org/10.1161/CIRCRESAHA.116.309307
  48. Ikeda G, Santoso MR, Tada Y, et al. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J Am Coll Cardiol 2021;77:1073-88. https://doi.org/10.1016/j.jacc.2020.12.060
  49. Jung JH, Ikeda G, Tada Y, et al. miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury. Basic Res Cardiol 2021;116:19.
  50. Lee JR, Park BW, Kim J, et al. Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair. Sci Adv 2020;6:eaaz0952.
  51. de Mendonca L, Felix NS, Blanco NG, et al. Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension. Stem Cell Res Ther 2017;8:220.
  52. Liang OD, Mitsialis SA, Chang MS, et al. Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension. Stem Cells 2011;29:99-107. https://doi.org/10.1002/stem.548
  53. Jiang L, Song XH, Liu P, et al. Platelet-mediated mesenchymal stem cells homing to the lung reduces monocrotaline-induced rat pulmonary hypertension. Cell Transplant 2012;21:1463-75. https://doi.org/10.3727/096368912X640529
  54. Kanki-Horimoto S, Horimoto H, Mieno S, et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation 2006;114:I181-5. https://doi.org/10.1161/CIRCULATIONAHA.105.001487
  55. Luan Y, Zhang X, Qi TG, Cheng GH, Sun C, Kong F. Long-term research of stem cells in monocrotaline-induced pulmonary arterial hypertension. Clin Exp Med 2014;14:439-46. https://doi.org/10.1007/s10238-013-0256-3
  56. Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymal stem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats. Basic Res Cardiol 2010;105:409-17. https://doi.org/10.1007/s00395-009-0065-8
  57. Umar S, de Visser YP, Steendijk P, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. Am J Physiol Heart Circ Physiol 2009;297:H1606-16. https://doi.org/10.1152/ajpheart.00590.2009
  58. Liu J, Han Z, Han Z, He Z. Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension. Exp Ther Med 2015;10:1657-64. https://doi.org/10.3892/etm.2015.2722
  59. Alencar AK, Pimentel-Coelho PM, Montes GC, et al. Human mesenchymal stem cell therapy reverses Su5416/hypoxia-induced pulmonary arterial hypertension in mice. Front Pharmacol 2018;9:1395.
  60. Lee H, Kim KC, Choi SJ, Hong YM. Optimal dose and timing of umbilical stem cells treatment in pulmonary arterial hypertensive rats. Yonsei Med J 2017;58:570-80. https://doi.org/10.3349/ymj.2017.58.3.570
  61. Zhang Y, Liao S, Yang M, et al. Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant 2012;21:2225-39. https://doi.org/10.3727/096368912X653020
  62. Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 2014;12:26.
  63. Zhang C, Wang P, Mohammed A, et al. Function of adipose-derived mesenchymal stem cells in monocrotaline-induced pulmonary arterial hypertension through miR-191 via regulation of BMPR2. BioMed Res Int 2019;2019:2858750.
  64. Klinger JR, Pereira M, Del Tatto M, et al. Mesenchymal stem cell extracellular vesicles reverse sugen/hypoxia pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2020;62:577-87. https://doi.org/10.1165/rcmb.2019-0154OC
  65. Aliotta JM, Pereira M, Wen S, et al. Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res 2016;110:319-30. https://doi.org/10.1093/cvr/cvw054
  66. Komaki M, Numata Y, Morioka C, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther 2017;8:219.
  67. Salomon C, Ryan J, Sobrevia L, et al. Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One 2013;8:e68451.
  68. Zhang Z, Ge L, Zhang S, et al. The protective effects of MSC-EXO against pulmonary hypertension through regulating Wnt5a/BMP signalling pathway. J Cell Mol Med 2020;24:13938-48. https://doi.org/10.1111/jcmm.16002
  69. Willis GR, Fernandez-Gonzalez A, Reis M, et al. Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. J Extracell Vesicles 2020;9:1790874.