Page 21 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 2 of 33

tract symptoms to progressive life-threatening viral and alveolar type II (AT2) cells. Under normal condi-
pneumonia and progressive hypoxemia requiring mech- tion, the AT2 cells secrete surfactant covering all the lin-
anical ventilatory support. The leading cause of mortality ing epithelium to facilitate alveolus expansion. AT1 and
in COVID-19 patients is hypoxemic respiratory failure AT2 are tightly connected with tight junctions, which
most frequently resulting in ARDS, characterized by dif- control the transfer of ions and fluid across the epithe-
fuse lung damage with edema, hemorrhage, and intra- lium. The endothelial cells of the blood capillaries are
alveolar fibrin deposition [6, 7]. More interestingly, la- connected by intercellular junctions and control the in-
boratory findings indicate a hyperactivated nature of the flux of inflammatory cells and fluid into the interstitial
immune system, specifically high levels of circulating space between the aveoli. Initially, the spike glycoprotein
CD4 + and CD8 + lymphocytes. Looking at the hyper- (S protein) expressed on viral envelopes binds to the
active immune response detected in COVID-19 patients, angiotensin-converting enzyme 2 (ACE2) receptor [11],
several potential treatments relating to key immunoregu- a very similar structure to that of SARS; however, with a
lators have been proposed. Another important factor in- 10–20 times much higher binding affinity when com-
fluencing the prognosis of COVID-19 patients is having pared to the SARS S protein [12]. This binding capability
a state of hyperinflammation, where several immunosup- partially explains the high transmission of SARS-CoV-2
pression modalities have provided a tool to decrease the [12]. The main target cells for SARS-CoV-2 infection are
mortality in patients with severe condition [8]. Under- AT2 cells and resident alveolar macrophages, because
standing the pathogenesis of SARS-CoV-2 in association they are expressing ACE2. SARS-CoV-2 utilizes ACE2
with the host immune response will help elucidate some for entry and the serine protease TMPRSS2, which is
key targeted treatment options. Repurposing of previ- also expressed by the alveolar cells, for S protein priming
ously approved medications, such as the anti-malarial [13]. This activation induces chemokine and cytokine se-
drug hydroxychloroquine, anti-rheumatic drugs, such as cretion that recruits inflammatory and immune cells into
tocilizumab (interleukin [IL]-6 receptor inhibitor), bari- the infected alveoli, followed by other waves of cytokine
citinib (Janus kinase [JAK] inhibitor), and anakinra (IL-1 release. Activated macrophages have a significant role in
receptor antagonist), have been employed to treat hemophagocytic lymphohistiocytosis (HLH)-like cyto-
COVID-19, largely attributed to their known pharmaco- kine storm during COVID-19 [14]. Secondary HLH
kinetic and safety profiles [9]. could be precipitated by a genetic defect in cytolytic
Mesenchymal stromal/stem cells (MSCs) offer a promis- pathways or observed in during infection, malignancy,
ing emerging therapeutic approach toward modifying the and rheumatic disease. HLH is characterized by a pre-
adverse effects of the infection in SARS-CoV-2 patients. dominance of inflammatory cytokines and expansion of
This therapy has been found to decrease the cytokine tissue macrophages displaying hemophagocytic activity
storm and exert anti-inflammatory, immunomodulatory, [15]. Cytopenias, a state of elevated inflammatory cyto-
and regenerative functions by altering the expression of kines or hypercytokinaemia, unremitting fever, elevated
pro-inflammatory cytokines, and aid in repairing the dam- ferritin level, and multi-organ damage, are among the
aged tissues in COVID-19 patients. Several clinical trials key characteristics of HLH seen in seriously ill COVID-
have already provided a proof of concept showing that 19 patients [8]. Type I interferons (IFN) and natural
intravenous (IV) infusion of MSCs is a safe option and killer (NK) cells result in cytolytic immune responses,
could lead to clinical and immunological improvement in following a successful recognition of pathogen-
some patients with severe COVID-19 pneumonia [10]. associated molecular pattern. This serves as a first
Such findings support employing phase 2 randomized line of defense against SARS-CoV-2 infection through
controlled trial, where other randomized trials with a con- the innate immune system. Activated cytotoxic T cells
trol arm consisting of standard treatment, will help to and B cells are key players of the adaptive immunity
elucidate the mechanistic potential of MSC-based thera- helping with viral clearance via destruction of virus-
peutic strategy. This review summarizes the immuno- infected cells and antibody production, respectively.
pathogenesis of the SARS-CoV-2 and the therapeutic However, when the anti-viral immune response re-
potentials of MSCs for treating lung injuries associated mains active, an aberrant and uncontrolled production
with COVID-19. Furthermore, we highlight the current of inflammatory cytokines occurs, causing what is
clinical trials using MSCs for treating COVID-19 patients known as the “cytokine storm”, leading to damage in
and discuss limitations of the existing MSC-based treat- the pulmonary tissue [16, 17].
ment strategies. Severely ill COVID-19 patients, especially the ones
with pneumonia, show disproportionate immune profile,
Pathogenesis of SARS-COV-2 with considerably lower lymphocyte counts (lymphocy-
The lung alveoli are lined with the alveolar epithelium topenia) and increased concentrations of inflammatory
consisting of a monolayer of alveolar type I (AT1) cells cytokines. Among the significant inflammatory