Written by: Krystal, Chongqing Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
Pulmonary hypertension (PAH) is a disease that eventually leads to right-sided heart failure by remodeling pulmonary blood vessels, with a very poor prognosis. Pulmonary hypertension (PAH) affects 70 million people worldwide. Conventional treatment can control symptoms, delay deterioration, and make great strides in improving long-term survival and quality of life, but pulmonary hypertension is not completely curable, so effective treatment strategies are still needed.
Recently, based on stem cells and their exosomes, epigenetic drugs and gene therapies, new ideas have emerged in preclinical research on the treatment of pulmonary hypertension. A review published in the Korean Circulation Journal explores the feasibility and prospects of stem cells and exosomes in the treatment of pulmonary hypertension [1]. Preclinical studies have proved the effectiveness of stem cells and exosomes in the treatment of pulmonary hypertension, and it is believed that with the further development of clinical trials, stem cells and exosomes are expected to open a new chapter in the clinical treatment of pulmonary hypertension.
Image from the literature [1]: The main role of stem cell and exosome therapy
Basis for stem cell therapy for pulmonary hypertension
Stem cells are cells that have not yet differentiated in the human body and have the potential to differentiate into any type of cell. Stem cells are able to differentiate into vascular cell lineages and can be effectively used in the regenerative process and treatment of pulmonary vascular regeneration for pulmonary hypertension. Mesenchymal stem cells (MSCs), derived from the mesoderm in the early developmental stages, can self-renew and have the potential ability to differentiate into multiple cell types, and are the most commonly used stem cell types in clinical treatment studies for pulmonary hypertension.
Mesenchymal stem cells have anti-inflammatory effects as well as modulating immune effects, and can also promote lung tissue regeneration. Pulmonary hypertension often presents with a decrease in resident mesenchymal stem cells in the lungs, and the administration of differentiated lung mesenchymal stem cells can slow the progression of pulmonary hypertension.
Several preclinical studies have demonstrated [2-3] that mesenchymal stem cells can control immune inflammation, thereby improving diseases such as acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. In the hypoxic model, it was found that mesenchymal stem cells had superior effects in improving right ventricular function, pathological changes, cell transplantation, and anti-inflammatory. These stem cells modulate the immune-inflammatory response in hypoxia models, thereby improving the environment in which stem cells live and increasing the survival rate of stem cells. Stem cells with improved survival can continue to function for a long time, reduce the inflammatory response, weaken vascular remodeling in pulmonary hypertension models, and improve hemodynamic function.
Induced pluripotent stem cells (iPSCs) are dedifferentiated cells of adult somatic cells with pluripotency. Induced pluripotent stem cells are another type of stem cell that has been applied to clinical studies of pulmonary hypertension to improve vascular remodeling, repair damage, and restore vascular endothelial integrity in pulmonary hypertension.
In the rat pulmonary hypertension model, the use of induced pluripotent stem cells improved right heart dysfunction and reduced the hemodynamic parameters of right ventricular systolic blood pressure. In addition, histologically, induced pluripotent stem cell therapy prevents worsening of vascular remodeling of pulmonary arterioles and inhibits the proliferation of the mesangial layer by blocking inflammation [4].
From the literature [1]: Therapeutic role of stem cells in pulmonary hypertension
Basis for the treatment of pulmonary hypertension by exosomes
Exosomes are extracellular vesicles that play a key role in the remodeling process of pathological vascular diseases and play a central role in therapeutic approaches in the clinical field. Observed at the molecular level, one of the main mechanisms leading to pulmonary vascular remodeling is the inflammatory response, which is responsible for the dysfunction of the immune system. Dysregulated immune cells recruit many mediators that lead to cascading harmful immune responses, and the transporters in these processes are extracellular vesicles.
From the literature [1]: Therapeutic role of stem cell-exosomes in pulmonary hypertension
In recent years, more and more literature has demonstrated that exosomes can be applied to vascular diseases including pulmonary hypertension. Exosomes regulate and control the main pathological signaling processes of disease progression at the molecular level, promote tissue regeneration and prevent disease progression.
Exosomes have a number of adhesion membrane proteins that can be used for tissue targeting localization. In addition, they have resistant membrane proteins to aid hoarding and anchoring, and may improve various alternative transplants in patients with cardiovascular disease. To date, more than 200 exosome clinical trials are underway or completed, but further research is needed to ensure the long-term stability of exosomes as therapeutic agents.
epilogue:
Although the use of targeted drugs has improved the prognosis of pulmonary hypertension, pulmonary hypertension remains a fatal progressive disease. The application of stem cell therapy has opened up new horizons for the treatment of pulmonary hypertension, but stem cell therapy has many difficulties to overcome in the technical steps of isolation, survival, and transplantation. From the results of existing preclinical studies, the effectiveness of stem cell therapy has been seen. In the future, it is believed that regenerative medicine-related therapies will open a new chapter in the treatment of pulmonary hypertension.
bibliography:
[1] Oh, S., Jung, J. H., Ahn, K. J., Jang, A. Y., Byun, K., Yang, P. C., & Chung, W. J. (2022). Stem Cell and Exosome Therapy in Pulmonary Hypertension. Korean circulation journal, 52(2), 110–122. https://doi.org/10.4070/kcj.2021.0191
[2] Glassberg, M. K., Minkiewicz, J., Toonkel, R. L., Simonet, E. S., Rubio, G. A., DiFede, D., Shafazand, S., Khan, A., Pujol, M. V., LaRussa, V. F., Lancaster, L. H., Rosen, G. D., Fishman, J., Mageto, Y. N., Mendizabal, A., & Hare, J. M. (2017). Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest, 151(5), 971–981. https://doi.org/10.1016/j.chest.2016.10.061
[3] Braza, F., Dirou, S., Forest, V., Sauzeau, V., Hassoun, D., Chesné, J., Cheminant-Muller, M. A., Sagan, C., Magnan, A., & Lemarchand, P. (2016). Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma. Stem cells (Dayton, Ohio), 34(7), 1836–1845. https://doi.org/10.1002/stem.2344
[4] Huang, W. C., Ke, M. W., Cheng, C. C., Chiou, S. H., Wann, S. R., Shu, C. W., Chiou, K. R., Tseng, C. J., Pan, H. W., Mar, G. Y., & Liu, C. P. (2016). Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension. PloS one, 11(2), e0142476. https://doi.org/10.1371/journal.pone.0142476