Stem Cells, Part of the Innate and Adaptive Immune Systems, as an Antimicrobial for Coronavirus Covid-19.

China is in a state of emergency, with 76,936 infections and 2,442 deaths from Covid-19. China’s leader, Mr. Xi has said, coronavirus Covid-19 is the “the fastest spread, the widest scope of infections and the greatest degree of difficulty in controlling infections” of any public health emergency since the founding of the People’s Republic of China in 1949. With 600 cases in S. Korea, parts of Northern Italia now on lockdown because of an outbreak there with 132 new cases, 7 deaths in Iran with Pakistan and Turkey having closed their borders with Iran – people are scarred (NY Times, Coronavirus update, 2020-02-23).

So how do we best fight this spreading, deadly disease? Public health measures are our first line of and most important means of defense in this newly emerging epidemic. The development of new antimicrobials is another means of potentially fighting this infectious agent. And stem cells, and the molecules that stem cells release may be an important new means of developing such antimicrobial therapeutics. Although premature, stem cell treatments in clinical trials for Covid-19 infections are currently underway in China. Why would anyone think that stem cells can fight a viral infection such as Coronavirus Covid-19? Let’s have a quick look why. But first, a quick why  not. Stem cell transplants cause the tissue in the host to age; specifically, the very cells needed to fight the infection, the T-cells, have been found to express markers for advanced aging following bone marrow stem cell transplants (Wood et al, 2016). Therefore the immune system that is needed to fight the Coronavirus infection may be compromised by the stem cell transplant. This doesn’t happen when the molecules from the stem cells are used instead of the stem cells themselves (Maguire, 2019).

Now for the rationale. First, as part of the innate immune system, stem cells release peptides, known as antimicrobial peptides (AMPS) (Esfandiyari et al, 2019) that have been found to fight viral infections (Hsieh and Hartshorn, 2016). Stem cells are activated by viral infections to release these AMPs, and, interestingly, the stem cells themselves are protected from the viral infection and remain normally active cells even when infection affects the tissue compartment in which the stem cell resides (Wu et al, 2018).

Now, here’s some new and very powerful research suggesting that stem cells are part of the adaptive immune system. Drs. Shruti Naik, Ph.D. at NYU and Elaine Fuchs, Ph.D. at Rockefeller University found that if patches of skin in mice were wounded, causing inflammation, then allowed to heal, subsequent wounds in the same patch of skin would heal about 2.5 times more quickly than adjacent, previously unwounded skin. The effect in previously wounded skin could last up to six months given the conditions of the experiment. This functional adaptation was attributed to epithelial stem cells (EpSCs) and did not require a canonical immune response because skin-resident macrophages and T cells were not involved. What the study found was that EpSCs maintain chromosomal accessibility, where the DNA is less tightly packed and open to signals from the damaged tissue, at key stress response genes, activated by the inflammatory stimulus. This epigenetic change in the chromatin allowed, during a secondary inflammatory challenge to the same skin patch, genes in that patch of skin to be transcribed rapidly. While the secretome of skin stem cells has previously been shown to be altered by wounding, the exact nature of changes in the secretome was not reported in this study. However, underlying the memory of the stem cells in this study is Aim2, a portion of DNA that encodes an activator of the inflammasome, a conglomerate of proteins that contributes to the skin’s defense against bacteria and viruses. An emerging area of research is quickly expanding as scientists continue to explore stem cell memory, and the field of immune-stem cell interactions, and stem cells as a part of the immune system. The stem cell functions described here also means that your health is not just genetic. What you do, including wounding yourself or having an infection may have long term consequences to your health. And optimizing your health, including through diet, will minimize the negative consequences of these wounding events or infectious events, including viral infections (Maguire, 2020).

Wu and colleagues discovered that stem cells are hardwired to express antiviral interferon-stimulated genes (ISGs), which help them fight viral infections. Further, β-glucan, a bacterial and fungal cell wall component induced IL-1β release, which was capable of training both hematopoietic stem cell (HSCs) and myeloid progenitors. These conditioned HSCs and myeloid progenitors were able to more efficiently ward off inflammatory challenges when compared to naïve HSCs. Further, IL-1β-trained HSCs exhibited dramatic changes in their energy metabolism, displaying augmented glycolysis and cholesterol biosynthesis, adjustments that turned out to be critical for conferring downstream functional changes in β-glucan-dependent HSC training (Mitroulis et al., 2018). Combine this stem cell training with conditioning of the canonical adaptive immune cells, T-cells, through a high fiber diet that induces a allostatic state (Sterling, 2020) and is pro-resolving for viral infections (Trompette et al, 2018). What I’m describing here is a “systems therapeutic” for “physiological renormalization” (Maguire, 2019) so that the body can better fight the viral infection and more quickly and efficiently resolve the ensuing inflammation that induces much of the damage to the body.

So what can you do now why scientists are working on new antimicrobial therapeutics to fight Coronavirus Covid-19? First, follow public health measures as instructed by your local health authorities. Second, eat well, including a predominantly whole food plant based diet that includes soluble and insoluble fiber that will set the immune system in a state to better fight the infection and resolve the inflammation (Trompette et al, 2018; Maguire, 2020) and may induce mechanical autophagy in the gut to help clear infection (King, 2012). Like stem cells that release a rich variety of antioxidant types (Hong et al, 2019), eating predominantly plants will also provide a rich variety of antioxidants to setup the antioxidant cascade (Villanueva and Kross, 2012) to help quell the viral infection (Beck, 2001; Crump et al, 2013). More on this subject can be found in my book, Thinking and Eating for Two (Maguire, 2020).

References

Beck MA (2001) Antioxidants and viral infections: host immune response and viral pathogenicity. J Am Coll Nutr. 20(5 Suppl):384S-388S.

Crump KE et al (2013) Antioxidant Treatment Regulates the Humoral Immune Response during Acute Viral Infection. J. Virology, DOI: 10.1128/JVI.02714-12.

Esfandiyari R et al (2019) Performance evaluation of antimicrobial peptide ll-37 and hepcidin and β-defensin-2 secreted by mesenchymal stem cells. Heliyon. 2019 Oct; 5(10): e02652.

Hong HE et al (2019) Antioxidant action of hypoxic conditioned media from adipose-derived stem cells in the hepatic injury of expressing higher reactive oxygen species. Annals of Surgical Treatment and Research 97(4):159.

Hsieh IN and Kevan L. Hartshorn KL (2016) The Role of Antimicrobial Peptides in Influenza Virus Infection and Their Potential as Antiviral and Immunomodulatory Therapy. Pharmaceuticals (Basel). 2016 Sep; 9(3): 53.

King JS (2012) Mechanical stress meets autophagy: potential implications for physiology and pathology. Trends in Molecular Medicine, DOI:https://doi.org/10.1016/j.molmed.2012.08.002

Maguire G (2020) Physiological renormalization using systems therapeutics. Future Sci OA. 2020 Jan; 6(1): FSO428

Maguire G (2019) Transplanted stem cells survive a long time: do they make you sick? J Roy Soc Medicine, https://doi.org/10.1177/0141076819851657.

Maguire G (2020) Thinking And Eating For Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts. Berkeley Free Speech Press, Berkeley, CA.

Mitroulis I et al. (2018). Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell 172, 147–161.e12.

Naik S et al (2017). Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480.

Sterling P (2020) What Is Health?: Allostasis and the Evolution of Human Design. MIT Press, Cambridge, MA.

Trompette A,  Gollwitzer ES, Pattaroni C et al. (2018) Dietary fiber confers protection against flu by shaping Ly6c − patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 48(5), 992–1005.

Villanueva C and Kross RD (2012) Antioxidant-Induced Stress. Int J Mol Sci. 2012; 13(2): 2091–2109.

Wood WA et al (2016) Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging. EBioMedicine. 2016 Sep; 11: 227–238.

Wu X, Dao Thi VL, Huang Y, Billerbeck E, Saha D, Hoffmann H-H, Wang Y, Silva LAV, Sarbanes S, Sun T, et al. (2018). Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172, 423–438.e425.

Published by Dr. Greg Maguire, Ph.D.

Dr. Maguire, a Fulbright-Fogarty Fellow at the National Institutes of Health, is a scientist, innovator, teacher, healthcare professional. He has over 100 publications and numerous patents. His book, "Adult Stem Cell Released Molecules: A Paradigm Shift To Systems Therapeutics" was published by Nova Science Publishers in 2018.

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