Academy KOL: Mesenchymal Stem Cell Therapy for COVID-19 (Dr. Miguel Garber, Spain)

Dr. Miguel G. Garber, (6-05-20202)
Ending of 2019, numerous cases of serious respiratory infections were reported in
Wuhan, China, a new coronavirus. Currently, the virus has been called SARS-CoV-2
virus and the World Health Organization (WHO) called the associated disease
COVID-19. This disease has caused doctors and researchers from different
branches of biomedicine to mobilize to find a solution or treatment for the
management of this pandemic. According to a recent announcement by the
International Society for Stem Cell Research (ISSCR) and SEMERETEC, Spanish
Societies for Regenerative Medicine and Cell Therapy, President Dr. Miguel G.
Garber, still there are not currently treatment no approved, approaches based on cell
therapies for the Prevention and treatment of COVID-19 infection present as an
option. However, recently, in several countries, mesenchymal stem cell (MSC)
treatments have introduced one of the therapeutic approaches to use in the
treatment of COVID-19 [1-2]. As we know, MSCs face viral infection due to the
presence of specific cytokines that enhance qualities. These characteristics are
present in MSCs in the intrinsic niche before their separation process occurs.
Therefore, MSCs can be expected to survive even if transplanted into a patient with a
confirmed COVID-19.
Coronaviruses (CoV) are a large family of viruses that some of them are better
known, such as Middle East respiratory syndrome (MERS-CoV) and severe acute
respiratory syndrome (SARS-CoV), but some of them are no known as the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

SARS-CoV-2 is a single-stranded (nucleocapsid) RNA virus with a sequence identity
of 79.6% equal to SARS-CoV 1 [6] as known as the largest discovered RNA viruses
by approximately 30 kb in the length of gene structure. It was first isolated using
human airway epithelial cells [7], but can be isolated from bronchoalveolar lavage
fluid from a COVID-19 patient [6,7]. In general, both SARS-CoV and SARS-CoV-2
are easily isolated and grow in Vero cells [7,8] [9]). Furthermore, this virus like
SARS-CoV enters its host cell by binding to the receptor for angiotensin-converting
enzyme 2 (ACE2) [10,11]. On March 11, 2020, the World Health Organization (WHO)
characterized the spread of COVID-19 as a pandemic [12].

Several studies have shown that the first stage of the pathogenesis of this type of
virus is the identification of the receptor for the anangotensin-converting enzyme 2
(ACE2) by its peak protein [17]. For this reason, ACE2 positive cells are infected [17].
Another study has shown that the cellular protease TMRRSS2 is also required to
allow entry of coronavirus into host cells [18]. It is conceivable that the AC2 receptor
is widely distributed on the surface of human cells, especially alveolar type 2 (AT2)
and capillary epithelium, and AT2 cells largely express TMPRSS2 [18]. On the other
hand, bone marrow, lymph nodes, thymus, spleen, and immune cells, such as T and
B lymphocytes and macrophages, are always negative for ACE2 [19]. These findings
suggest that immunoglobulin therapy may help patients with the virus infection. The
current hallmark of SARS-CoV-2 pathogenesis is the cytokine storm. Acute release
of virus-activated cytokines from GSCF, IP10, MCP1, MIP1A, IL-2, IL-6, IL-7, and
TNF results in lung edema, air exchange dysfunction, acute respiratory distress
syndrome (ARDS ) and acute cardiac injury, and leading to death [2].
To date, there is no specific cure for Covid-19, although the clinical management of
these patients currently includes infection prevention and control, supportive care,
including supplemental oxygen, and mechanical ventilation support when necessary.
Recently, on the viral surface glycoprotein, several epitopes, including 5 CTL
epitopes, 3 sequential B celllepitopes, 5 discontinuous immune cell B cell epitopes
[20] and 13 MHC-I and 3 MHC-II antigenic epitopes [21] ], it has been reported
through the immunoinformatic approach that some of these epitopes may have
potential candidates for the development of 2019-nCoV vaccines

Mesenchymal stem cell therapy


Currently, cell-based therapy and especially stem cell therapy has become a
promising therapeutic field, in which many opportunities to cure incurable diseases
[22]. Despite significant development in the field of stem cell-based therapy,
immunogenicity, limited cellular source, and ethical issue as the main limitations of
this therapeutic approach have not yet been resolved. Among these, the MSCs have
attracted attention due to the significant potential, a high proliferation rate, being a
non-invasive procedure and without ethical problems. There is a great
preponderance in the use of MSC therapy compared to other treatments [23], given
that:
I. They are easily accessible and can be isolated from various tissues such as
bone marrow and adipose tissues, including the umbilical cord, the dental
pulp, menstrual blood, etc .;
II. They are multipotent stem cells;
III. MSCs can easily expand to clinical volume in a suitable period of time;
IV. MSCs can be stored for repetitive therapeutic use;
V. Clinical trials of MSC so far have shown no adverse reactions to allogeneic
MSC;
VI. The safety and effectiveness of MSCs have been clearly documented in
clinical trials [23].

COVID-19, can trigger an immune overreaction in the body.
In COVID-19 patients, the immune system produces large amounts of inflammatory
factors, which cause a cytokine storm, including an overproduction of immune cells
and cytokines [24]. Here is the beginning of the idea of MSC therapy in treatment.
Probably, MSC therapy can prevent the release of cytokine storms by balancing the
immune system and promoting endogenous repair by the reparative properties of
stem cells. After intravenous injection, part of the MSC population is trapped in the
lung as the first filter, but here these MSCs could re-coat the lung microenvironment,
protect alveolar epithelial cells, intercept lung fibrosis, and cure lung dysfunction. and
COVID-19 pneumonia [25]. MSCs can be isolated from different adult tissues,
including bone marrow (BM), peripheral blood (PB), and fatty tissues (AT) (such as
abdominal fat) and tissues associated with neonatal delivery, including the placenta
(PL), the umbilical cord (UC), Warton’s jelly (WJ), amniotic fluid (AF), and umbilical
cord blood (CB), and then stored for possible future applications and for clinical trials
or at least the combination treatment for treat patients with COVID-19.

fascinatingly, one of the available methods to evaluate its efficacy in the maintenance
or repair of damaged vital organs is the use of mesenchymal cell therapy (MSC) that
is widely used in the treatment of type 2 diabetes, autoimmune disease, injury of the
spinal cord, GVHD and several others Diseases especially with high immunity rates
have been used [23,26-28]. MSCs, using their immunomodulatory properties and
their differentiation capacity, can prevent the death of lung tissue by counteracting
the cytokinestorm and the regeneration and reconstruction of damaged tissues.
Recently, the use of these cells has also been suggested in the clinical treatment of
viral H5N1 infections that have similar effects on the lung [29].
Conclusion
The immunomodulatory and anti-inflammatory properties of MSCs in the treatment of
respiratory diseases were confirmed by more than 15 complete clinical studies, and
more than 70 trials in this regard were also registered (https://clinicaltrials.gov). The
umbilical cord, umbilical cord blood, Wharton’s jelly, menstrual blood, dental pulp and
MSCs produced by the company are important sources of MSC that will be used in
various clinical trials. However, the process of developing new therapeutic therapies
and their clinical application has important practical implications and is not over for
COVID-19 MSC therapy. The clinical use of MSC therapy to treat COVID-19 is still
absent, but there are some promising reports of treatments performed that justify
applying cell therapies. Stem cell therapy and especially MSCs may be one of the
most ideal therapies or a combination of treatment to treat patients with COVID-19.

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Z. (2020). A new coronavirus associated with humanrespiratory disease in China.Nature, 579(7798), 265–
269.https://doi.org/10.1038/s41586-020-2008-3.2.

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