Page 79 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Pain Physician: August 2020 COVID-19 Special Issue 23:S391-S420

nor specific anti-HLA antibodies to MSCs. However, and 0.9%) or IA (0.8% and 0.6%) injection. Very few
it should be emphasized that Unlike umbilical cord cells were seen in organs despite IA administration.
blood, which has very few MSCs, the Wharton jelly In another study, after IV infusion of MSCs, scinti-
presents a rich source. Because the umbilical cord is graphic images revealed an uptake of 5.4%, 4.3%,
considered a medical waste, it can be easily obtain- and 2.3% of the total infused radioactivity in the
able and is a plentiful source of MSCs. Even though heart after 1, 3, and 24 hours, respectively (28). The
umbilical MSCs share many surface markers and the remaining activity was distributed mainly to the
superior proliferative/differentiation capabilities of liver, spleen, kidneys, and bladder at all time points.
embryonic MSC, unlike embryonic MSCs, they are not Intraorgan injections, especially highly vascularized,
known to be tumorigenic. Hence umbilical MSCs may do not seem to enhance engraftment. Akker et al
be well positioned for culture expansion to create an (29) have shown that during direct intramyocardial
“off-the-shelf” product. administration, substantial numbers of MSCs were
To treat organ failure, intravenous infusion of immediately flushed out of the heart via the venous
MSCs seems to be the most commonly used route system within a few heart beats after the start of
due to its easy accessibility and straightforward injection. In another study, after IV infusion, MSCs
approach. Intraarterial administration has been at- were detected in the lung within 30 minutes and
tempted to increase engrafting of the cells in the remained detectable after 24 hours, after which
organ. Direct injection into the organ has also been uptake was detected in the liver, spleen, and bone
utilized, however, it has the disadvantage of being marrow up to 7 days postinfusion (30). However,
an invasive procedure and leading to poor cell distri- when MSCs were injected into the avascular lumbar
bution through the lesion. Furthermore, a growing disc, they not only survived for 8 months, but also
body of evidence indicates that cells do not need to duplicated, differentiated into chondrocytes, and
enter the organ to produce a therapeutic effect, and produced collagen and extracellular matrix (ECM)
very few cells remain in the organ in studies that use (31). Using the IA approach, although very few
IV or IA administration. Instead of direct cell replace- cells remain in the targeted organ, their number
ment, the functional effects of MSC therapies seem is higher than IV administration, albeit transiently.
to be mainly due to antiinflammatory and immuno- Whether this translates to better clinical outcomes
modulatory properties and the release of trophic fac- is unknown. IA transplantation decreased the “first
tors (26). Although the mechanism of action of cell bypass” effect of bone marrow MSCs in the lungs
therapy remains elusive, there is compelling in vitro and increased uptake in other organs, especially in
evidence that transplanted cells modulate the func- the liver, spleen, and kidneys (32). Most of the IV-
tion of various immune cell types via release of host infused cells are cleared from the circulation within
paracrine factors directly or through vehicles, such as 5 minutes, and almost all of them are entrapped in
extracellular vesicles (27). the lungs primarily because MSCs are relatively large
The fate of injected MSCs have been tracked in cells and express various adhesion molecules (33). A
animal and human studies (27). When injected intra- small number reappear in the circulation after a lag
venously, after 2 hours, the MSCs are mostly seen in period of approximately 10 minutes, probably after
the lungs (20.9%), liver (13.5%), kidneys (3.2%), and release from the lung. Only a miniscule number
spleen (2%). After 24 hours, the MSCs concentration reaches the target organ and disappears by day 3
decreased in the lungs (7.8%), but increased in the (27). In another study, the number of accumulated
liver (18.5%), kidney (7%), and spleen (3.2%). Very cells in the lung decreased significantly from 6 hours
few cells are seen in other organs. In the same study, after transplantation and continued to diminish to
MSCs were injected into the middle cerebral artery. 2% or less by day 10 (32). However, although there
After 2 hours, most of the cells were found in the liver were fewer cells in the liver and spleen, 2 hours af-
(40.6%), followed by the lung (7.1%), spleen (5.8%), ter the infusion, the levels gradually increased with
and kidney (4.2%). After 24 hours, the cell numbers time and had the highest signals by day 10. In one
increased slightly in the liver (46.9%), spleen (6.5%), study, the MSCs fell exponentially, with a half-life of
and kidney (7.6%), but decreased in the lung (4.3%). approximately 24 hours and practically completely
Interestingly, very few cells were noted in the brain disappeared after 4 days (32). An overwhelming ma-
2 hours or 24 hours later, irrespective of IV (0.8% jority of cells die soon after transplantation . More

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