Written by: Yang, Fujian Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
Since the outbreak of the epidemic, many countries have used stem cells in the exploration of treatment options, and stem cell treatment of new crown pneumonia has become a hot topic. Recently, the Ministry of Science and Technology of the People's Republic of China issued the 2022 annual project declaration guidelines for key special projects such as "stem cell research and organ repair", according to the previously released application guidelines (draft for comments), the key special projects cover stem cell treatment of new crown pneumonia and other related fields.
Previously, mesenchymal stem cells (MSCs) have been shown to have great potential in the treatment of lung diseases such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and chronic obstructive pulmonary disease.
In recent years, scientists have tried to use MSCs in the new crown pneumonia, which is also mainly manifested by lung damage. In addition, angiotensin-converting enzyme 2 (ACE2) has been shown to be a receptor for SARS-CoV-2 to enter target cells. MSCs, on the other hand, do not express ACE2 and are resistant to SARS-CoV-2 infection. Therefore, MSCs-based treatments may be promising for PATIENTS with COVID-19, especially those with severe and critical illnesses [2].
Today we will take a look at what progress has been made by mesenchymal stem cells in the treatment of new crown pneumonia?
Multiple potential mechanisms for MSCs to treat COVID-19
Mesenchymal stem cells can be obtained from most human tissues such as bone marrow, fat, umbilical cord, and placenta. Mesenchymal stem cell therapy relies primarily on its ability to self-renew, multi-potential differentiation, low immunogenicity, anti-inflammatory function, and the ability to homing damaged tissues. In addition, mesenchymal stem cells have unique immunomodulatory mechanisms to modulate innate and acquired immune responses[2]. Mesenchymal stem cells have shown positive signals in research to treat COVID-19, and experiments have shown that they mainly work through the following mechanisms:
01
#分化潜能
Previous studies have shown [3] that MSCs may have the ability to transdifferentiate into alveolar epithelial cells. In addition, transplanted MSCs were found to differentiate into respiratory epithelial cells to compensate for the functional alveolar epithelial cell barrier in diseased tissues and to improve local damage.
The domestic team found that transplanting type 2 alveolar epithelial cells induced by human umbilical cord mesenchymal stem cells into a mouse model of lung fibrosis can reduce pulmonary fibrosis and mortality. The main target of the new coronavirus is the alveolar epithelium, so because MSCs have the potential to differentiate into alveolar epithelial cells, they are thought to be useful for the treatment of lung damage and inflammation caused by SARS-CoV-2 infection.
02
#免疫调节
The immunomodulatory properties of MSCs are well known for regulating innate and acquired immunity by interacting with a variety of immune cells. In addition, due to the immune escape mechanism of SARS-CoV-2, the virus partially evades recognition and attack by the natural immune system, so acquired immunity plays a key role in killing the virus. MSCs regulate acquired immunity primarily by targeting T lymphocytes, B lymphocytes, antigen-presenting cells (APCs), DCs, NK cells, and regulatory T cells (Tregs).
In addition, local immunity in the lungs is mediated by CD4+ T cells and CD8+ T cells, which can rapidly kill foreign viruses in the event of infection, suggesting that the adaptive immunomodulatory mechanisms of MSCs are a key link in the treatment of COVID-19 [2].
03
#分泌抗炎因子
Inhibiting inflammation is another important function of MSCs, which secrete a variety of soluble anti-inflammatory factors through paracrine action. The study found that a variety of inflammatory factors in the blood of patients with new coronary pneumonia, such as interferon-γ, interferon-inducing protein-10, monocyte chemotactin-1, etc. were elevated.
Furthermore, elevated levels of inflammatory factors are more pronounced in those with severe and critical illness [5]. COVID-19 causes a cytokine storm and secretes high levels of pro-inflammatory cytokines in the lungs, such as IL-1β, IL-1RA, and IL-2. Therefore, the powerful secretion of anti-inflammatory factors by MSCs can effectively inhibit the above inflammatory response, which is mediated by the production of anti-inflammatory molecules and inhibition of the secretion of inflammatory factors.
04
#抗病毒及抗凋亡
In patients with new crown pneumonia, different degrees of apoptosis can be observed, including lung epithelial cells and immune cells, and whether the apoptosis of these cells can be reversed has become the key to controlling the occurrence and development of diseases. Mesenchymal stem cells have the ability to resist apoptosis and inhibit apoptosis due to hypoxia, chemical stimulation, mechanical damage and radiation, a property that has been demonstrated in alveolar epithelial damage models. Therefore, the anti-apoptotic properties of MSCs for lung disease mean that MSCs can be used to treat COVID-19 [2].
Image from literature[2]
MSCs inhibit viral replication, viral shedding, and virus-induced lung epithelial cell damage[2]. However, the mechanism by which MSCs inhibit SARS-CoV-2 replication and infection is unclear and further research is needed.
There are NEW CROWN patients at home and abroad who benefit from MSC treatment
A large number of previous studies have shown that MSCs transplantation has the potential to help patients with severe COVID-19 recovery, and clinical trials are currently being conducted in research institutions in many parts of the world. So far, a search on ClinicalTrials.gov website has found that there are currently 96 clinical trials using MSCs to treat COVID-19. Among them, cord cord, bone marrow and adipose tissue are the main sources of MSCs for clinical trials to treat COVID-19, most of which are in the early stages.
In the past two years, clinical research results on the treatment of new crown pneumonia by mesenchymal stem cells have been published at home and abroad.
In China, a multi-center, open-label, non-randomized, parallel-controlled exploratory trial [6] conducted by Academician Li Lanjuan's team and others studied the efficacy of menstrual-derived mesenchymal stem cells in the treatment of new coronary pneumonia, of which 26 patients received allogeneic, menstrual-derived MSC treatment and drug therapy (experimental group), and 18 patients received only drug therapy (control group). The results showed that the case fatality rate in the MSC group was significantly lower than that in the control group (7.69% and 33.33%). Patients with dyspnea and oxygen saturation improved significantly on days 1, 3, and 5 after MSC infusion. In addition, the chest imaging results were also significantly improved within 1 month. The incidence of adverse events did not differ between the MSC group and the control group.
Image from the literature[6]
Abroad, in a Phase 1/2a double-blind randomized controlled trial conducted by a team in the United States[7], 24 patients with COVID-19 were randomized to the cord mesenchymal stem cell (UC-MSC) treatment group (n = 12) or control group (n = 12) in a 1:1 ratio, followed by a one-month follow-up. The results showed that no serious adverse events related to UC-MSC infusion were observed; the infusion of UC-MSC consistently and effectively reduced the level of inflammatory cytokines associated with the covid-19 cytokine storm; the survival rate of the group receiving UC-MSC was significantly improved (91% vs. 42%, P=0.015); and the recovery time of the UC-MSC treatment group was significantly shortened (P=0.0307).
Image from literature[7]
Reflections on the development of future clinical research
A large number of previous studies have preliminarily confirmed the efficacy of mesenchymal stem cells in the treatment of new crown pneumonia, which has also promoted the development of many clinical trials. However, current clinical trials are still in their early stages, and more clinical data is needed in the future to further elucidate potential mechanisms and potential targets to improve clinical applications.
Secondly, the sources of mesenchymal stem cells used in the current research are diverse, and there is no agreement on what type of stem cell type to use, what dosage to use and what route of administration, and it is waiting for unified standards to be developed in the future.
At the same time, exosomes derived from mesenchymal stem cells are believed to have similar functions with stem cells, and some obstacles to the clinical application of stem cells can be avoided, and whether they can be applied to the treatment of new crown pneumonia is worth studying.
The exploration of mesenchymal stem cells for the treatment of new crown pneumonia is still continuing, and with more results exported, this field will surely develop faster.
Bibliography:
[1]https://www.who.int/emergencies/diseases/novel-coronavirus-2019
[2] Chen L, Qu J, Kalyani FS, et al. Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci. 2022;79(3):142. Published 2022 Feb 20.
https://pubmed.ncbi.nlm.nih.gov/35187617/
[3] Harrell CR, Sadikot R, Pascual J, et al. Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives. Stem Cells Int. 2019;2019:4236973. Published 2019 May 2.
https://pubmed.ncbi.nlm.nih.gov/31191672/
[4] Liu J, Peng D, You J, et al. Type 2 Alveolar Epithelial Cells Differentiated from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Mouse Pulmonary Fibrosis Through β-Catenin-Regulated Cell Apoptosis. Stem Cells Dev. 2021;30(13):660-670.
https://pubmed.ncbi.nlm.nih.gov/33899513/
[5] Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.
https://pubmed.ncbi.nlm.nih.gov/32361250/
[6] Xu X, Jiang W, Chen L, et al. Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med. 2021;11(2):e297.
https://pubmed.ncbi.nlm.nih.gov/33634996/
[7] Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660-673.
https://pubmed.ncbi.nlm.nih.gov/33400390/
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