Page 57 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 3 of 19

environment within the lung enhances the production of In 2017, Caplan suggested that the name “mesenchy-
reactive oxygen species, impairs lung barrier function, mal stem cells” be changed to “medicinal signaling cells”
increases vascular permeability, promotes the accumu- to more accurately ref ect the fact that, in vivo, these cells
lation of alveolar proteinaceous exudate and eventually secrete bioactive factors that are immunomodulatory and
results in pulmonary f brosis [21, 22]. trophic, meaning that these cells make medicinal drugs
T e neutrophils may migrate from inf amed tissues in situ [32]. Below we describe the mechanisms of action
to other organs causing widespread organ dysfunction. of mesenchymal stem cells (MSCs).
Neutrophils kill microorganisms by phagocytosis or the
release of neutrophil extracellular traps (NETs), which How do MSCs function?
are comprised of a core of chromatin DNA and histones MSCs are known to function via several mechanisms rel-
surrounded by proteases, reactive oxygen species-gener- evant to acute lung injury.
ating enzymes and anti-microbial proteins. T e excessive
NETs release directly damages lung tissues [23]. • When administered intravenously:
Current ef orts for the management and treatment
of this deadly disease remain supportive with ef orts to • MSCs sequester in the lung.
reduce ventilator-induced lung injury and permit an • MSCs are immune-evasive.
endogenous repair process to help with recovery from • MSCs are immune-modulatory.
lung injury. T ere is some evidence that neuromuscu-
lar blockade and prone positioning improves survival • Specif c mechanisms of therapeutic action:
in ARDS patients, but the evidence is not def nitive [24,
25]. Management with mechanical ventilation and f uid- • Anti-inf ammatory.
restriction provides organ support while minimizing iat- • Antibacterial.
rogenic harm [22]. Several pharmacological approaches • Antiviral.
have been tried including glucocorticoids, surfactants, • Lung f brosis inhibition.
inhaled nitric oxide, antioxidants and protease inhibitors. • Lung tissue regeneration.
Unfortunately, these treatments have been found to be • Anti-apoptotic of injured cells.
completely inef ective [26, 27]. Currently, no direct thera- • Alveolar f uid clearance.
pies for ARDS exist. • Extracellular vesicle production.

Mesenchymal stromal/stem cells (MSCs)
In 1968, Friedenstein et al. f rst isolated mesenchymal MSCs are abundant in adipose tissue and highly potent
stem cells from bone marrow (BM-MSCs), which was Human ASCs have signif cant advantages over MSCs
then termed a colony-forming unit f broblast (CFU-F) derived from other sources because they are obtained
[28]. T ese plastic-adherent bone marrow stromal cells from a minimally invasive lipoaspiration procedure
were denoted as CFU-F due to their f broblastic appear- [33]. T e MSC concentration in adipose is greater than
ance and ability to form colonies in vitro. In 1991, Caplan all other tissues in the body [34, 35] and the potency
termed these cells mesenchymal stem cells (MSCs) due to is maintained with age of the donor [36], unlike bone
their mesenchyme origin during embryonic development marrow derived MSCs [37, 38]. Signif cant numbers of
noting an ability to dif erentiate into osteoblasts, adipo- ASCs can be obtained due to accessibility to the subcu-
cytes, and chondrocytes [29]. In response to the varying taneous adipose tissue and the volume that can easily
nomenclature used to characterize MSCs, in 2005 the be extracted. Taken together, the ASC has advantages in
International Society of Cellular T erapy (ISCT) pro- both autologous use and allogeneic use. Signif cant anti-
posed that these stromal cells be referred to as multipo- inf ammatory ef ects have been conf rmed in many vet-
tent mesenchymal stromal cells and the term be reserved erinary and human clinical studies [39–41].
for cells that meet the following criteria [30, 31]:
Infused MSCs are sequestered in the lung
1. Plastic adherence in standard culture conditions. Intravenous infusion of MSCs are known to accumu-
2. Surface marker expression of CD105, CD73 and late in the lungs, a great benef t for treatment of pulmo-
CD90. nary disease, where they secrete numerous paracrine
3. Lack expression of CD45, CD34, CD14 or CD11b, factors that can play a signif cant role in protecting or
CD79 or CD19 and HLA-DR. rejuvenating alveolar epithelial cells, counteract f brosis
4. Dif erentiation potential toward osteoblasts, adipo- and improve lung function [42]. Following intravenous
cytes, and chondrocytes in vitro. administration, only a small fraction of MSCs engraft