By Brigitte Hanly
While humanity braces itself under the extraordinary pressure of a global pandemic, world scientists are uniting. We are all sharing and bringing forth our best understanding of the situation, in order to design effective and lasting solutions. All intelligence is now on deck and it is time for stem cell science to contribute. The FDA has recently approved clinical trials of stem cell therapy for COVID-19 end-stage sufferers as part of their compassionate use programs (1). The FDA has also approved the use of stem cell-derived natural killer cells (2). Regulatory doors are ﬁnally opening, rightly due to the well established immunomodulatory & regenerative properties of stem cells. An exploration of the stem cell mechanism of action is due in the context of COVID-19.
Adult Stem Cells
The most studied and widely used stem cells are called adult stem cells. These adult stem cells are a small population of cells that can be found in most organs of the human body. Their role is to recognize tissue injury, to repair, and to restore normal function. This is achieved via numerous mechanisms, some of which are secretory signaling and differentiation into specialized somatic cells. They reside in niched areas of each organ and lay low, divide and age with us until they are called for duty.
Stem cells’ capacity to differentiate into specialized cells is not the most signiﬁcantly interesting part of their therapeutic use. What scientists now understand is that by harvesting stem cells and transplanting them into the blood ﬂow or into damaged tissue, either that of the donor or that of the recipient, these stem cells express their unique undifferentiated DNA and secrete molecules that the other cells of the body have forgotten to express. This secretome, constituents packaged in exosomes, is the key therapeutic tool that is harnessed in stem cell therapy.
Regardless of whether the stem cells are autologous (from the recipient) or allogeneic (from a donor), all have a window of just a few hours during which they express their secretome into the tissue environment and signal the tissue cells to modify their activity. After a few hours, once they differentiate and become specialized, they cease to express stem cell exosomes and are either integrated into the body, if they carry the same DNA as the recipient (autologous), or expelled by the immune system in the case they carry foreign DNA (allogenic). The secretome is speciﬁc to stem cell type and to the tissue environment.
Adult stem cells from adipose tissue, also called mesenchymal stem cells, will release exosomes that reﬂect a speciﬁc code-restriction status since the epigenetics of their DNA is such that they can only differentiate into bone, skin, fat, conjunctival and cartilage cells. The hematopoietic stem cells from the bone marrow will release different exosomes to that of mesenchymal stem cells, as their DNA has a different type of code-restriction, predisposing them to differentiate into blood cells.
The exosomes released by stem cells will also depend on the recipient tissue status. For instance, if there is runaway inﬂammation in the area, the released exosomes will address this particular loss of immune allostasis and express a composition that is physiologically relevant. For this reason, we still prefer stem cell transplantation (cellular) over exosome therapy (acellular), since the composition of the secretome is most therapeutic when precisely coded for the speciﬁc challenges of the tissue physiology at hand.
Pluripotency of Stem Cells
As a stem cell scientist, I’ve chosen to study and develop the application of the most potent and comprehensive type of stem cells, namely pluripotent stem cells. These cells originate in a blastocyst, the very early stage of an embryo. They come to maturity 5 days after the fusion of an egg and aspermatozoa. Pluripotent stem cells could be called the mother of all cells, the mother of all stem cells. From the original 150 pluripotent stem cells in a blastocyst, arise trillions of cells that make up the human body.
While the adult stem cells have a code-restricted DNA, the DNA of pluripotent embryonic stem cells is unrestricted and expresses a much wider variety of micro-RNAs, reaching all tissue for repair and restoration.
From my 15 years of laboratory and clinical experience with pluripotent stem cells, I and my entire scientiﬁc and clinical team have observed that pluripotency has a much wider range of applications than other stem cells. These stem cells are capable of restoring organs in a way that other adult stem cells cannot, including the brain and the nervous system which are the most challenging organs to repair (3).
Stem Cells in COVID-19
Early published reports on COVID-19 severity postulate that hyperinﬂammation is what is driving the rapid onset of respiratory distress. Under this cytokine release syndrome model, high levels of inﬂammatory cytokines and chemokines are released into pulmonary vascular endothelium. Inﬂammatory monocytes and aberrant Th1 cells enter pulmonary circulation and cause immune damage to the lungs, leading to acute lung injury (ALI) and acute respiratory disease syndrome (ARDS). This precipitates sepsis, multi-organ failure, functional disability and rapid mortality (4,5).
A recent Lancet article suggests that the use of corticosteroids or Janus Kinase (JAK) inhibitors which are usually considered in hyperinﬂammation are inadvisable for patients with COVID-19 (8). This is logical, as they would lead to broad immunosuppression and therefore leave the viral load free to multiply. The key to helping late-stage patients is to provide a tool that would reduce the hyperinﬂammation without attenuating the capacity of the immune system to ﬁght viral invasion. This is where stem cell science has a role to play.
Stem cells have an immune regulatory effect in hyperinﬂammation. They not only suppress the proliferation of CD4+ cells but they also suppress the secretion of various cytokines like IL-2, IL-12, IFN¬γ, TNF-α, IL-4, IL-5, IL-1β, and IL-10 which are involved in the hyperinﬂammation. However, the TGF¬beta cytokine and the enzyme IDO which are both involved in the modulation of the immune system are not affected by the stem cells (9). In other words, stem cells lower the inﬂammatory response while regulating the T cell production so that the ﬁght against the virus can be maintained.
More recent reports are expanding our physiological understanding of the deeper causes of the COVID-19. The damage within the lungs may not be solely due to an inﬂammatory storm, but also due to the metabolic debris of the infection. When COVID-19 symptoms worsen, a rapid drop in hemoglobin levels is observed in severely affected patients (6). Using computer models, scientists postulate that the ORF8 protein and surface glycoproteins of the SARS-CoV-2 could bind to the 1-Beta chain of the hemoglobin forcing the dissociation of the iron atom at the center of the porphyrin molecule of the heme. The damaged hemoglobin would then be rendered incapable of carrying oxygen and that could explain the hypoxemia (7). This hypothesis is still to be conﬁrmed.
The observed decrease of hemoglobin level that contributes to the severe hypoxemia of COVID-19 sufferers could be addressed with the administration of erythropoietin to stimulate the production of red blood cells (10). Infusion of stem cells would also activate the production and differentiation of erythropoietic stem cells into erythrocytes along with the other hematopoietic stem cells.
Another way to address anemia is by transfusion of Packed Red Blood Cells. The pandemic is putting excess pressure on the national blood supply. Blood suppliers have warned hospitals about the high demand and the challenges in restocking the blood bank. Interestingly, a study published in 2012 showed that it is possible to derive red blood cells from human embryonic stem cells in vitro in a very efﬁcient way (11). Since embryonic stem cells can be cultured indeﬁnitely from a single blastocyst, in a time of pandemic, they could prove to be a safe and renewable source of red blood cells.
Stem cells also minimize the long-term complications that may await survivors of COVID-19. Hypoxemia, or below-normal oxygen levels in the blood observed post severe respiratory distress, may lead to multi-organ system failure. The heart, kidneys, and brain function may be severely impaired by the prolonged lack of oxygen and hyperinﬂammation. Stem cells, especially pluripotent stem cells administered intravenously to people with organ failure, have the capacity to assist the body in reversing such damage. Pulmonary ﬁbrosis is a long term complication to expect as well. Lung damage has been reported even in asymptomatic carriers (12). In our clinical experience, pluripotent stem cells have a high afﬁnity for lung tissue and are effective in helping to repair lung injury and scarring (3).
Finally, the area where I foresee the most long term stem cell involvement is in the ﬁght against immunosenescence. In his latest article, Zhavoronkov describes COVID-19 as a gerophilic infection, and even more signiﬁcantly a gerolavic infection, more harmful to the elderly (13). The higher severity and lethality of the infection observed in the population aged 60 and above is due to the aging of the immune system, a general loss of functions in all organs including the thymus. After the age of 50, the thymus is made up of mainly ﬁbrotic tissue and the number of T cells produced decreases signiﬁcantly. This epigenetic senescence is the ultimate target of all age reversal protocols and pluripotent embryonic stem cells have a major role to play in this endeavor.
Our clinical studies have shown clear improvements of most physiological function in the elderly receiving pluripotent stem cells, a decrease of their biological age, and measurable elongation of their telomere length. In recent studies, David Sinclair and colleagues have been able to restore the vision of old mice with glaucoma using embryonic stem cells genes (OSK) for epigenetic reprogramming (14). They also show that the epigenetic information of youth is kept in the old cells and can be restored via what they call REVIVER, the recovery of information via epigenetic reprogramming. With regular infusions of embryonic stem cells, the OSK and NANOG genes are expressed and reprogramming of the aged cells can take place, restoring healthy function and strengthening immunity.
“Pre-existing conditions, including diabetes, CVD, hypertension, obesity, and other consequences of an unhealthy lifestyle are also associated with increased mortality, indicating that the biological age is more relevant than the chronological age” David Sinclair (15).
Society is experiencing a massive shift. Our daily lives are being disrupted, yet global crises have proven to act as catalysts for innovation. Studies in China and Israel have already shown success in the use of stem cells for patients with severe ARDS (16). The FDA just allowed their use in a few expanded access programs in the US. Stem cells science is ﬁnally making headway in supporting patients suffering from COVID-19 here and now. I believe that the next beautiful challenge is to make that intelligence more widely available in prevention, treatment, and rejuvenation so that the next pandemic is met with a majority of epigenetically young and healthy subjects who have the bioresilience to keep on living an active and vibrant life, rising to any challenge.
(4) Yonggang Z. et al. Pathogenic T cells and inﬂammatory monocytes incite inﬂammatory storm in severe COVID-19 patients. National Science Review. 2020 https://doi.org/10.1093/nsr/nwaa041
(5) Mehta PM et al., COVID-19: consider cytokine storm syndromes and immunosuppression. https://doi.org/10.1016/S0140-6736(20)30628-0
(6) G. Lippi et al, http://www.htct.com.br/en-hemoglobin-value-may-be-decreased…
(7) Wenzhong, L. et al., COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv, 2020.
(8) A.Ritchie, Immunosuppression for hyperinﬂammation in COVID-19: a double-edged sword?https://www.thelancet.com/…/PIIS0140-6736(20)30691…/fulltext
(9). KH Han et al., ”Immunosuppressive mechanisms of embryonic stem cells and mesenchymal stem cells in alloimmune response” Transplant immunology 25(1) 7-15, 2011 https://www.sciencedirect.com/…/a…/abs/pii/S0966327411000438
(10) A Hadadi et al, Does recombinant human Erythropoietin administration in critically ill COVID‐19 patients have miraculous therapeutic effects? Journal of virology, https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25839
(11) Y Ebihara et al, Generation of red blood cells from human embryonic/induced pluripotent stem cells for blood transfusion, Int.J.Hematol., https://www.ncbi.nlm.nih.gov/pubmed/22648827
(12) Studies proﬁle lung changes in asymptomatic COVID-19, viral loads in patient samples, https://www.cidrap.umn.edu/…/studies-proﬁle-lung-changes-as…
(13) A Zhavoronskov, Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections. https://www.ncbi.nlm.nih.gov/pubmed/32229705
(14) Y Lu et al, Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming , http://dx.doi.org/10.1101/710210
(15) D Sinclair, Biomarkers of biological age as predictors of COVID-19 disease severity, https://doi.org/10.1101/808642
(16) Z Lang et al, Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia, http://www.aginganddisease.org/EN/10.14336/AD.2020.0228