An international team reported on a novel mechanism of stem cell therapy for COVID-19
An international team, including key members of the International Society on Aging and Disease (ISOAD http://isoad.org/ ) recently published new findings concerning the effects of mesenchymal stem cells on COVID-19 patients. The team was led by Prof. Robert Zhao of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College. The study entitled “Mesenchymal Stem Cell Treatment Improves Outcome of COVID-19 Patients via Multiple Immunomodulatory Mechanisms” was published in the prestigious scientific journal Cell Research. https://www.nature.com/articles/s41422-021-00573-y
COVID-19 is now widely considered the No.1 enemy of global public health. Despite the unprecedented global epidemiological measures, most of all massive vaccinations, the constantly emerging drug-resistant strains of the virus still occasionally break through the defenses of the epidemic prevention. Moreover, re-infection of COVID-19 in vaccinated people has occurred in all countries. Yet, novel coronavirus specific drugs are not yet available. Crucially, the treatment of severe and critically ill COVID-19 patients remains a major unresolved challenge for mankind. The current situation shows that the fight against the epidemic cannot only rely on vaccines. There is still the urgent task for medical science to develop practically effective drugs specifically for COVID-19. Only by combining prevention and treatment, can we be well prepared.
The scientific team engaged in the emergency research of COVID-19 treatment immediately after the outbreak of the epidemic, in early 2020. Building on the unique biological role of mesenchymal stem cells (MSCs) in the regulation of the immune system and their earlier work in the treatment of various immune diseases, the team offered a new method to combat the pathogenic characteristics of COVID-19 patients who died of multiple organ failure due to their own immune system dysfunctions. The team was the first to propose the idea of using MSCs to treat COVID-19, combining experts from various fields of clinical research, biogerontology, statistics, stem cell research and other fields, and establishing a working collaboration of over 20 clinical diagnosis and treatment institutions. A clinical study of the treatment of COVID-19 with umbilical cord mesenchymal stem cells was carried out between January and February 2020 in two hospitals in Beijing. Encouraging clinical results were achieved: all the patients who received MSCs treatment tolerated it well and were discharged from hospital successfully. The results were published in the scientific journal Aging and Disease of the International Society on Aging and Disease. Being the first published study on this subject, it was since then quoted over 750 times. http://www.aginganddisease.org/EN/10.14336/AD.2020.0228
In the new published study, the team summarized a completed randomized, single-blind, placebo-controlled Phase II clinical trial of MSCs for COVID-19, including 58 COVID-19 patients (22 males and 36 females, including 21 severe and 6 critical cases). The results of the clinical study demonstrated a significant efficacy of the MSC treatment: MSC infusion rapidly and significantly improved the prognosis of severe and critically ill patients, alleviating symptoms such as cough, chest distress and dyspnea and improving chest imaging results. It shortened the median time for symptom relief. Follow-up chest imaging showed a greater improvement in patients with severe or critical disease in the MSC treatment group compared with the placebo group. Moreover, the treatment was associated with a shorter hospital stay (11 days vs. 15 days). It improved characteristic markers of the disease: decreased the levels of C reactive protein and various pro-inflammatory factors, such as plasma IL-1RA, IL-18, IL-27, IL-17E/IL-25 and other inflammatory cytokines. The MSC treatment resulted in a prolonged persistence of COVID-19 antibodies. It prevented thrombosis shown by a decrease in plasma neutrophil extracellular traps or “NETs” (extracellular web-like structures composed primarily of chromatin fibers and microbicidal granule components). Essentially, the patients in the MSC treatment group had a good therapy tolerance and were discharged from hospital without any adverse reactions, indicating a good safety of MSC treatment. The death rate was zero in the MSC group and 6.9 percent in the placebo group.
The results clearly show that MSCs can significantly improve the outcome of COVID-19 severe and critically ill patients, mitigate their symptoms and enhance their immune function indicators, in particular to restrain the cytokine storm in vivo. Thus, the results suggested a new treatment strategy for COVID-19 patients, with reduced side effects, besides the existing approaches, such as convalescent serum, antiviral, hormonal and non-hormonal anti-inflammatory treatments.
Moreover, this study conducted a comprehensive panel of experiments in order to clarify the therapeutic mechanisms of MSCs in the treatment of COVID-19. The experiments, including in vitro as well as animal experiments, further elaborated the mechanism of MSCs regulation of the immune molecular network for restoring the immune system homeostasis in COVID-19 patients. Thus, this study, for the first time, performed high-throughput RNA sequencing (scNA-SEQ) on peripheral blood mononuclear cells (PBMC) from COVID-19 patients treated by MSCs. The results further demonstrated the complex mechanism by which MSCs modulated the immune response in these patients. The study proposed that, in COVID-19 patients, a temporary extramedullary hematopoietic microenvironment was formed after MSCs therapy, which supported self-renewal and differentiation of hematopoietic stem cells in vivo and provided feasible conditions for the subsequent activation of the peripheral immune function. Among other biological effects, the study discovered that MSCs treatment facilitated the aggregation of immune cells to inflammatory sites; increased the expression of telomerase related genes in immune cells; and regulated the proportion of B cell subsets. Moreover, MSC treatment increased the expression of CD28 – a costimulatory molecule in T cells, and thus promoted T cell function. This study was also the first to confirm that MSCs can promote chemotactic migration and maturation of immune cells such as Dendritic cells, T cells and B cells by upregulation of specific genes in COVID-19 patients, which play an important role in regulating immune function and rebuilding immune homeostasis in the patients.
Further research was done on the immune regulation of MSCs in animal models that was able to promote the repair of lung tissue injury in mice. It was shown that MSCs can effectively induce an immune response after the lung tissue injury in a group of mice treated by MSC-LPS, significantly diminishing the inflammatory reaction, such as neutrophils and macrophages infiltration in the lung interstitial tissue, and reducing the acute lung injury. The increased expression of CD38 on B cells suggested that MSCs may promote the activation of B cells. The above changes of immune cells suggested that MSCs can effectively induce a robust immune response after lung injury in the model, which is specific to the immune cell types and can be beneficial for regulating the inflammatory response and repair of damaged lung tissue.
Overall, this study conducted a comprehensive, in-depth, detailed mechanistic analysis of the clinical safety and effectiveness of MSCs in the treatment of COVID-19. The mechanisms of action involved immunomodulatory effects at different biological levels and dimensions, including molecular, cellular, model animal and clinical trials. Essentially, the study provided a comprehensive experimental foundation for the vast application potential of MSCs in the treatment of intractable diseases characterized by immune dysfunctions, such as COVID-19. It provided a candidate drug product with an industry-level development potential for clinicians and pharmaceutical industry. More importantly, it has provided a new strategic tool to fight against COVID-19.
The international team involved in this study included key members of the International Society on Aging and Disease (ISOAD) including experts from China, the United States, Britain, France, Italy, Russia, Spain, Israel, India, South Korea, and other countries, involving more than 20 biomedical laboratories and research organizations. Thus, this study will help strengthen the interdisciplinary international collaborative innovation and promote the development of science and technology globally.
Altogether, the results of this study reflected the integration of modern medicine and traditional Chinese medical concepts. MSCs was shown to remodel the immune function, reverse inflammatory pathology, and improve the therapy rate. It revealed that MSCs therapy for COVID-19 is based on the compound anti-inflammatory and immunomodulatory functional effects.