Page 44 - Read Online

Page 8 of 9 Xu et al. Vessel Plus 2023;7:33 https://dx.doi.org/10.20517/2574-1209.2023.98

benefit might have been seen if a less severe form of cardiac injury (such as ischemia-reperfusion) had been
employed instead of permanent coronary artery ligation. On a different note, one may wonder whether
there was any uptake of EVs by any organs after IV injections. Our previous studies have shown that there
was significant hepatic uptake of EVs after IV administration; despite hepatic uptake after IV injection,
there were no detectable differences in liver inflammation, fibrosis, or proliferation, which may be because
this was not a liver disease model [7,8,14] . The main value of the negative hepatic findings is a grossly negative
side effect profile to the liver tissue after IV HBMSC-EV injection, an increasingly common and non-
invasive EV delivery method.

Secondly, how should studies showing improvement in cardiac function after systemic administration of
EVs be interpreted when no significant cardiac uptake of EVs has ever been shown? One study systemically
injected a porcine model of acute MI (via left circumflex artery ligation) with a 1,000 µg of mesenchymal
stem cell-derived EV protein twice daily for 7 days following MI, and they achieved a clear reduction of
[3]
infarct size (30%-40%) on cardiac MRI . Cardiac MRI is a highly accurate modality and thus the
improvements in cardiac function can be believed. However, one significant caveat to this study is the
massive dose of the EVs used, which may not be practical given the vast quantity of cells, labor, supplies,
and equipment needed to produce EVs - this would make the clinical use of EVs highly expensive and time-
consuming for any benefit to be achieved. It is definitely possible that some EVs are taken up in the heart, as
the current EV biodistribution detection methods such as fluorescent molecular tomography are not very
[7]
sensitive, in that smaller IM EV doses are not detected . Thus, if EVs are to be successfully transitioned to
clinical use, more refined administration techniques will be needed or the cardiac-homing properties of EVs
will need to be amplified.

9
In conclusion, a single-dose administration of neither IM nor IV injection of 2 × 10 HBMSC-EV particles
in a murine myocardial infarction model resulted in significantly improved cardiac function. This
necessitates studies aimed at improving cardiac delivery by developing bioengineered EVs with cardiac or
organ-specific delivery properties. The main limitation of this study is the lack of optimization of HBMSC-
EV dose testing to see if increased doses or multiple doses could result in a post-MI cardiac benefit.
However, the current study suggests that in order to treat cardiovascular disease efficiently in clinical
settings - future studies are required to optimize EV dosage and administration routes, and/or bioengineer
EVs to render cardiac-homing properties.

DECLARATIONS
Authors’ contributions
Conceptualization, methodology: Xu CM, Teixeira RB, Abid MR
Formal analysis: Xu CM, Faherty P, Abid MR
Funding acquisition: Sellke FW, Abid MR
Investigation: Xu CM, Broadwin M, Faherty P, Sabra M
Project administration: Xu CM, Abid MR
Supervision: Abid MR
Validation, writing - original draft preparation: Xu CM
Visualization: Xu CM, Faherty P
Writing - review & editing: Xu CM, Broadwin M, Faherty P, Teixeira RB, Sabra M, Sellke FW, Abid MR

Availability of data and materials
Upon request from the first author, Xu CM.