Page 47 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 28 of 33

and protocols [182]. Due to the trapping effect of MSCs several in vitro culturing strategies have been developed
occurring in the lung, a justification for the high doses to mimic the natural MSC niche, preserving the function
of MSCs has been proposed [183]. Therefore, MSCs and quality of a scalable clinical-grade cell expansion re-
could be genetically modified to overexpress selected main a challenge.
genes in order to increase in their engraftment. Pre- The adult sources of MSCs include painful and inva-
treatment with a series of preconditioning approaches sive procedures with possible donor site morbidity [195].
could also promote MSCs therapeutic effects and en- Regardless the origin, the MSCs display heterogeneity in
hance their survival in the lung. Of note, challenges with their abilities to propagate and differentiate [196]. The
autologous MSC transplantation in ARDS are demon- differences in the properties of MSCs are associated with
strated by their impaired potential due to the immuno- the variations in the age of the donor, method of MSC
modulatory effects of bone marrow MSCs [184]. isolation, and in vitro culturing approaches. As an alter-
As extracorporeal membrane oxygenation (ECMO) is native source, hPSCs could differentiate into unlimited
among the salvage therapy for refractory respiratory fail- number of MSCs, displaying MSC characteristics [55,
ure in the context of acute respiratory compromise associ- 197, 198]. Further studies are needed to extensively
ated with SARS-CoV-2, it is critical to learn how MSCs examine the differences between MSCs isolated from
would act in such setting [185]. IV administration of different tissues and those derived from hPSCs.
MSCs has been found to attach to membrane oxygenator A systemic procoagulant state has been observed in se-
fibers during ECMO in an in vitro ARDS model, leading verely ill COVID-19 patients, which tends to result in
to a significant decrease in the flow through the circuit poor outcome. Such patients are at high risk of dissemi-
[186]. Intratracheal and IV infusions of MSCs before nated intravascular coagulation (DIC) and thrombo-
ECMO or during a pause in the flow are some suggested embolism. Looking at the risk of hypercoaguable state in
strategies to overcome this limitation. Interestingly, a COVID-19 patients, the safety profile of MSCs could be
more recent study demonstrated an enhanced endogenous further challenged [199]. DIC and thromboembolism
MSC mobilization in patients with ARDS undergoing taking place after the administration of TF/CD142-ex-
ECMO [187]. Therefore, intratracheal administration of pressing MSC products have been reported [182]. The
MSCs might be an option in ARDS requiring continuous production of the highly procoagulant tissue factor TF/
high-flow ECMO. CD142 between products could vary. BM-MSCs have
The fate of MSCs after infusion also remains to be in- the lowest TF/CD142 expression, whereas ASC display
vestigated. Cell migration and distribution studies have the highest expression profile [182]. Finally, the dynam-
shown that the majority of MSCs localize to the lungs ics of the current pandemic and the rising global de-
after IV infusion [188, 189]. Intravascular arrest of MSCs mand highlight the need for scalable manufacturing
is due to MSC’s diameter ranging from 10 to 20 μm, big- required to provide enough doses of MSC product of
ger than the width of the pulmonary micro-capillaries high quality in a reproducible and timely manner.
[190]. However, following IV administration, MSCs still
tend to migrate to sites of injury and move from the Conclusion and future perspectives
lungs to other organs, such as the liver and spleen [191, MSCs have a potential therapeutic function in COVID-
192]. Nevertheless, challenges remain in interpreting this 19, which is displayed in their ability to enhance alveolar
data as this tracking could be detecting phagocytosed fluid clearance and promote epithelial and endothelial
MSCs. This is in line with the evidence showed that recovery through transfer of EV components together
most of MSCs become apoptotic after administration with the cell-cell contact as well as their secreted soluble
[193]. To avoid poor cell survival following MSC trans- factors. As ACE2 is widely expressed in other tissue
plantation, several preconditioning strategies have been types in addition to lungs, it is intuitive to consider MSC
proposed. Ang1-preconditioned cell survival was signifi- effect on the other organs as well. MSC treatment may
cantly increased via increased Akt phosphorylation. This reduce the progression of ARDS in severely ill COVID-
has further reduced the apoptotic rate in vitro via in- 19 patients with multiple organ failure.
creased expression of B cell lymphoma protein 2 (Bcl-2) Although several clinical trials have been recently reg-
and the ratio of Bcl-2/Bcl-associated X (Bax) [193]. Sev- istered to examine the safety and efficacy of MSCs as an
eral priming strategies with pharmacological agents, in- emerging therapeutic option for COVID-19-induced dis-
flammatory cytokines or mediators, hypoxia, and ease, fewer studies have been published. Learning from
biomaterial have been shown to enhance the therapeutic these clinical trials, MSCs could exert its immunomodu-
efficacy of MSC transplantation. MSCs enhanced traf- latory and regenerative capacity in COVID-19 patients.
ficking and homing to sites of injury is demonstrated in Although there is no approved treatment for COVID-19
the high expression of chemokine receptors, such as as of yet, MSC therapies continue to show improvement
CXCR4, CXCR7, and CX3CR1 [194]. Finally, although in the treatment of some of the leading causes of