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Mesenchymal stem cells and management of
COVID-19 pneumonia
Author links open overlay panelSu M.Metcalfe
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Abstract
Human coronavirus,
hCoV-19, is highly pathogenic with severe pneumonia associated with rapid virus
replication. Arising in Wuhan China December 2019, the current COVID-19
epidemic has rapidly grown with person-to-person infection expanding to become
a global health emergency now on pandemic scale.
In mitigation of
this current COVID-19 pandemic, according to Anderson et al. 2020 [1],
governments will not be able to minimise both deaths from COVID-19 and the
economic impact of viral spread. Keeping mortality as low as possible will be
the highest priority for individuals; hence governments must put in place
measures to ameliorate the inevitable economic downturn. The current global
picture shows small chains of transmission in many countries and large chains
resulting in extensive spread in a few countries, such as Italy, Iran, South
Korea, and Japan. Most countries are likely to have spread of COVID-19, at
least in the early stages, before any mitigation measures have an impact. The
scale of the problem is massive. Here I consider new approaches to improve
patient's biological resistance to COVID-19 using stem cells, and how benefit
might be scaled and simplified using synthetic stem cells to meet logistical
needs within a short time frame.
Keywords
Corona
virus
Cytokine
storm
Mesenchymal
stem cells
Leukaemia
inhibitory factor
Synthetic stem cells
1. Introduction
On
the clinical front, the two key requirements in the COVID-19 pandemic are to
reduce infection rate, and to decrease the death rate of those infected. Whilst
the majority of effort is aimed at infection, there is also need for clinical
research on how to best manage seriously ill patients with COVID-19 [1].
Current available therapies - including non-specific anti-virals, antibiotics
to treat secondary bacterial infections and sepsis, and corticosteroids to
reduce inflammation - fail in severe disease where the hallmark is the cytokine
storm induced by COVID-19 in the lung, visible as inflammatory lesions with
ground-glass opacity on CT scan. Virally-triggered acute cytokine release of
IL-2, IL-6, IL-7, GSCF, IP10, MCP1, MIP1A and TNFñ induces pulmonary oedema,
dysfunction of air-exchange, acute respiratory distress syndrome, acute cardiac
injury, and often secondary infection, leading to death.
The
Lancet has recently published the first comprehensive clinical data on risk factors
for COVID-19 mortality, with detailed clinical course of illness including
viral shedding that may continue in survivors up to 37â¯days [2].
In-hospital death is associated with age and notably IL-6 is a significant
correlate. For COVID-19, the case fatality rate (CFR) remains unknown until the
number infected is determined, but WHO estimates 0.3âÂÂ1%, which is higher than
0.1% for influenza A. The accruing epidemiological analyses, linked with
country-based mitigation strategies, and with estimates that about 80% COVID-19
patients have mild or asymptomatic disease, 14% severe disease, and 6%
critically ill, underpin a continuing need for treatment of COVID-19 pneumonia
in the long term.
2. Mesenchymal stem cells
Two
recent studies from China [3,4] have asked, can mesenchymal stem cells (MSC)
treat COVID-19 pneumonia, based on known immunomodulatory and reparative
properties of stem cells? Both studies reveal remarkable reversal of symptoms
even in severe-critical conditions. Accordingly, these clinical studies not
only identify a novel therapeutic strategy, but also the existence of natural
mechanisms able to counteract acute inflammatory pneumonia.
One
study is a case report of a critically ill COVID-19 patient on a ventilator who
had progressed despite intensive therapy, with markers showing evidence of
liver injury. This patient was treated with allogeneic human umbilical cord MSC
(hUCMSC) using three intravenous infusions of 5â¯ÃÂâ¯107 hUCMSC, three days apart. Within four
days of her first cell infusion, the patient was off the ventilator and able to
walk. All measured parameters, including circulating T cell counts, returned
towards normal levels â lymphocytes previously being low presumably due to
sequestration within the inflamed lungs and tissues. No obvious side effects
were observed [3].
The second study [4]
was a pilot clinical trial to assess whether MSC transplantation could improve
the outcome of 7 enrolled patients with clinical COVID-19 pneumonia, with one
critically severe, four severe, and 2 non-severe. Before transplantation, all
had high fever, shortness of breath, and low oxygen saturation. Treatment was a
single intravenous dose of clinical grade MSCs, 1â¯ÃÂâ¯106 cells per
kilogram of weight. Detailed follow-up over 14â¯days post-transplantation showed no adverse
effects, and within 2â¯days, all patients had significantly improved pulmonary
function, including the one severe COVID-19 pneumonia case who was well enough
for discharge by day 10. With full details presented, overall, after treatment
the peripheral lymphocytes increased with a shift towards the regulatory
phenotype for both CD4+ T cells and dendritic cells; and inflammatory cytokines
significantly decreased whilst IL-10 increased.
The clinical MSC
trial also asked if hCoV-19 infected the therapeutic MSC cells. hCoV-19 enters
cells through the ACE2 receptor widely distributed on human cells including
alveolar and capillary endothelium. The MSCs were ACE2 negative initially.
During follow-up, using RNA-seq survey to identify 12,500 transplanted MSC, it
was revealed that the cells had not differentiated and still remained ACE2
negative and thus presumed free from COVID-19. Moreover, and remarkably, gene
expression profiles of the recovered MSC showed high anti-inflammatory and
trophic factor activity including TGFò, HGF, LIF, VEGF, EGF, BDNF and NGF,
demonstrating that the immunomodulatory properties of the MSC are long-term and
actively maintained by continuing cytokine production.
However, whilst the
MSC studies identify a new approach to treat COVID-19 pneumonia, the
overwhelming numbers argue against cell therapy on logistical grounds. Here
novel approaches to capture the therapeutic properties of stem cells using
nanotechnology become of interest.
3. Synthetic stem cells â âÂÂLIFNanoâÂÂ
LIF
(leukaemia inhibitory factor) is known to be indispensable to oppose the
cytokine storm in the lungs during viral pneumonia (Fig. 1)
[5,6].
Although MSCs release LIF, this is not a practical source to meet numerical
need. Using nanotechnology synthetic stem cells are available as âÂÂLIFNanoâ with
1000 times increase in potency [7]. In a preclinical model of Multiple Sclerosis
(MS), the time lines of reversal of paralysis (4â¯days) are in accord with those reported for
COVID-19 pneumonia using MSC therapy (Fig.
2).
As an emerging alternative to cell-based therapy, nanomedicinals meet the need
for a high volume and off-the-shelf therapeutic agent able to rejuvenate
damaged tissues and suppress cytokine storm in pneumonia. Global distribution
is simple using low volume vials. Delivery can be inhalation or intravenous or
both.
1.
Download : Download
full-size image
Fig. 1. Influence of endogenous LIF
on responses to infection.
Adapted from Quinton et al. [6]. Previous Studies had shown that LIF is
particularly important for the epithelial STAT3 activating capacity of pneumonic
alveolar lining, and that treatment with exogenous LIF [9] or LIF over-expression [10] can limit pulmonary inflammation in
response to LPS or hyperoxia.
The Quinton experiment illustrated here investigates the
requirement for endogenous LIF to protect against acute
lung injury. Lungs were collected from mice 24â¯h after
intratracheal inoculation of Escherichia coli co-instilled
with anti-LIF or control IgG. (A): Representative images of intact freshly
isolated lungs and hematoxylin/eosin-stained lung sections. Red circles denote
infected left lung lobes. (B) Lung wet:dry weight ratios show effect of
anti-LIF treatment expressed as means ñ SEM. *pâ¯<â¯0.05
compared to mice treated with control IgG (nâ¯=â¯3âÂÂ5).
The anti-LIF resulted in LIF being undetectable, whilst the other cytokines
measured - GCSF, GM-CSF, IL-10, IL-17, IL-1ò, IL-6, KC,
MIP-2 - were not significantly altered by the anti-LIF treatment. (For
interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
1. Download
: Download full-size image
Fig. 2. Paralysis in an EAE model is rapidly
reversed by LIFNano therapy.
C57/Bl10
mice were immunised against myelin protein (MOG) resulting in paralysis of hind
limbs and tail by day 14: protocol was the Hooke model of experimental allergic
encephalopathy - this provides a standardised preclinical animal model of
Multiple Sclerosis.
Untreated:
Mice 15â¯days
post immunisation showing paralysis of hind limbs and tail.
Treated:
Mice treated identically and showing paralysis at 15d, then followed by 4â¯days
treatment with 1â¯mg/day
i.p. LIFNano-CD4 nanoparticles. There is a significant recovery of movement:
this improved further with prolonged therapy.
The
results are highly reproducible, and control nanoparticles without LIF cargo
targeted to CD4 had no effect on paralysis.
(This
study was part of an I-UK BMC Project âÂÂCELL-FREE REGENERATIVE MEDICINE:
Nano-Engineered âÂÂLIFNanoâ to treat Multiple Sclerosisâ PROJECT NUMBER: 102847).
4. Summary
and urgency
Whilst new vaccines to reduce infection rate of COVID-19
are being developed and scaled up, there is need to treat the significant
number of patients who develop pneumonia. The remarkable new data using MSC
demonstrate successful harnessing of natural endogenous pathways with powerful
protective properties. With age, growth factors associated with stemness
decline in favour of more inflammatory cytokines including IL-6 â a correlate
with in-hospital death resulting from COVID-19.
Considering needs for mitigation of the
current COVID-19 pandemic, with priority to keep mortality as low as possible,
the finding that MSC are safe and can reverse severe critical disease with high
potency is a major breakthrough representing an entirely new biological
approach to treatment that needs to be developed urgently. To this end, stem
cell biotech companies are joining forces (e.g., Athersys and Mesoblast) [8], whilst the nanotechnology-based
synthetic stem cell LIFNano is ready for cGMP production at scale today [7].
Funding
This research did
not receive any specific grant from funding agencies in the public, commercial,
or not-for-profit sectors.
CRediT authorship contribution statement
Su M. Metcalfe:Writing - original draft.
Declaration of competing interest
The author reports
no competing interests.
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