A study published in Aging and Disease shows the effectiveness of mesenchymal stem cell (MSC) therapy against a deadly immune reaction caused by COVID-19.

While scientists all over the world are working on a vaccine that would be effective against the SARS-CoV-2 coronavirus, which is responsible for the COVID-19 pandemic, a group of researchers from China and other countries has been exploring a therapeutic approach. Capitalizing on previous research, this group has conducted a successful trial of MSC therapy, resulting in the recovery of all seven patients [1]. These important results inspire hope, considering that a vaccine may still be more than a year away.

The perfect cytokine storm

The novel coronavirus, similarly to some other viruses, including SARS-2003, enters the host cell via the angiotensin converting enzyme 2 (ACE2) receptor on its surface [2]. ACE2 normally acts as a cardioregulator, so cells with ACE2 receptors are abundant in our blood vessels, and these receptors are present on the alveolar type II cells (AT2) in the lungs. This explains why the coronavirus attacks the capillary-permeated lungs along with other organs, such as kidneys, causing death in severe cases. However, the human body becoming suicidal is a major mortality factor [3], as every affected organ becomes a battlefield of our immune defenses against the virus. In the case of COVID-19, the very intensity of the battle may trigger a devastating immune overreaction. While fighting the virus, our immune system produces large amounts of inflammatory factors, causing a cytokine storm [4] – an overproduction of immune cells and their activating compounds (cytokines). Activated immune cells surge in numbers, causing severe inflammation throughout the body and fluid buildup in the lungs. This is likely to have been a leading cause of death during the infamous Spanish flu epidemic of 1918-1920.

Why MSCs?







Mesenchymal stem cells (also known as mesenchymal stromal cells) are multipotent cells that are able to differentiate into several cell types, such as bone, cartilage and fat. They are also known for their peculiar and powerful immunoregulatory abilities, which even made some scientists wonder whether MSCs should be considered immune cells [5]. These abilities caused MSCs to be featured in multiple recent studies of immune-related and age-related diseases, such as Alzheimer’s disease [6].

The numerous mechanisms that MSCs use for immunoregulation are still being studied, but we know that these cells play a vital role in balancing immune reactions. MSCs interact with most of the cell types of the immune system, including B cells, T cells, dendritic cells (DCs), natural killer (NK) cells, neutrophils, and macrophages, moderating their response to pathogens. Moreover, they do so only when stimulated by inflammatory cytokines, i.e. when inflammation levels are unacceptably high [7]. Importantly, MSCs do not have an ACE2 receptor, which makes them immune to SARS-CoV-2.

The study

The researchers recruited seven patients suffering from COVID-19: two with common infections, four with severe infections, and one with a critically severe infection; all of them were aged 45 to 65. There was also a placebo control group of three patients with severe infections. MSCs were intravenously transplanted to the study group patients. Over the course of the experiment (January 23 to February 16), one patient from the placebo control group had remained in severe condition, another one had developed acute respiratory distress syndrome (ARDS), and the third one died. In the study group, all patients with common and severe infections had recovered, while the critically ill patient was out of the ICU with a common infection. Although most COVID-19 patients eventually recover, it usually takes much longer, especially for critically ill patients.

The pulmonary function and symptoms of the seven patients significantly improved in just two days after MSC transplantation. The researchers documented a sharp decline in the levels of a major inflammation marker, C-reactive protein. The number of overreactive immune cells plummeted. The levels of TNF-α, a cytokine involved in systemic inflammation, went down as well, while the levels of the anti-inflammatory cytokine interleukin-10 (IL-10) increased. No adverse effects were observed, reinforcing MSCs’ reputation for safety. Performing as expected, the MSCs spectacularly succeeded in calming the patients’ cytokine storms.







Conclusion

This study underscores the fact that emerging therapies for age-related diseases enrich the trove of our medical knowledge and can be creatively used to target immediate threats. It gives hope to the thousands of current and future COVID-19 patients, as there is not yet any vaccine or any other confirmed treatment. This therapy can potentially be used against any disease that induces cytokine storms, including similar viruses that we may encounter in the future.

Literature

[1] Leng Zikuan, Zhu Rongjia, Hou Wei, Feng Yingmei, Yang Yanlei, Han Qin, Shan Guangliang, Meng Fanyan, Du Dongshu, Wang Shihua, Fan Junfen, Wang Wenjing, Deng Luchan, Shi Hongbo, Li Hongjun, Hu Zhongjie, Zhang Fengchun, Gao Jinming, Liu Hongjian, Li Xiaoxia, Zhao Yangyang, Yin Kan, He Xijing, Gao Zhengchao, Wang Yibin, Yang Bo, Jin Ronghua, Stambler Ilia, Wei Lim Lee, Su Huanxing, Moskalev Alexey, Cano Antonio, Chakrabarti Sasanka, Min Kyung-Jin, Ellison-Hughes Georgina, Caruso Calogero, Jin Kunlin, Chunhua Zhao Robert. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. , 2020, 0(0): 216-228







[2] Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission.SCIENCE CHINA Life Sciences.

[3] Ruan, Q., Yang, K., Wang, W., Jiang, L., & Song, J. (2020). Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine, 1-3.

[4] J. R. Teijaro, K. B. Walsh, S. Rice, H. Rosen, M. B. A. Oldstone. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proceedings of the National Academy of Sciences, 2014

[5] Hoogduijn, M. J. (2015). Are mesenchymal stromal cells immune cells?. Arthritis research & therapy, 17(1), 88.

[6] Ge, M., Zhang, Y., Hao, Q., Zhao, Y., & Dong, B. (2018). Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: A systematic review and meta‐analysis. Brain and behavior, 8(7), e00982.







[7] Wang, M., Yuan, Q., & Xie, L. (2018). Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem cells international, 2018.