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of py-STAT3 in human pulmonary arterial SMCs in response to hypoxia is inhibited by exosomes derived
from the human umbilical cord [124] . Klinger et al. [125] have recently reported the prevention and reversal
of the Sugen+ hypoxia model of PH in rats by MSC EVs. Similar to the cancer phenotype, in PAH, cells
undergo a metabolic shift towards glycolysis and lactic acid formation which enables sustained ATP
production and uncontrolled cell growth. MSC exosomes increase glucose oxidation and prevent a shift to
glycolysis and mitochondrial damage. In addition, exosomes inhibit SIRT4 expression upstream of pyruvate
dehydrogenase and glutamate dehydrogenase that contribute to the improvement of mitochondrial
function [126] . Thus, MSC-derived EVs can have beneficial effects on the pathophysiology of PH and
mitochondrial function.

PH is a frequent and serious complication in preterm infants with BPD, a chronic lung disease. Treatment
with conditioned media from cultured mouse bone marrow-derived MSCs showed significant improvement
in hyperoxia-induced BPD in mice. It reversed hyperoxia-induced lung parenchymal pathological changes
and PH [127] . Chang et al. [128] treated nine preterm infants (gestational age 25.3 ± 0.9 weeks) with intra-
tracheal transplantation of human umbilical cord blood-derived MSCs. At 7 days after treatment, these
infants had no adverse effects, and the severity of BPD was observed to be low. In addition, tracheal
aspirates revealed lower levels of IL-6, IL-8, metalloproteinase-9, TNFα and TGFβ1. These studies showed
the beneficial effects of MSCs on lung development.

In summary, EVs play a significant role in the pathophysiology of PH. Under normal conditions, EVs
produced by different cells modulate immune responses, participate in intercellular communication and
maintain homeostasis. Increased levels of EVs observed in PH are indicative of endothelial injury. These
EVs facilitate cell proliferation, inflammation, and progression of the disease. MSCs and MSC-derived EVs
are capable of modulating immune responses, repairing injured tissues and have regenerative properties.
The beneficial effects of MSCs and MSC-EVs, including some genetically modified MSCs have been
reported in several experimental models of PH. Treatment with MSC-EVs (naïve or genetically modified)
may have an advantage over cell therapy.

DECLARATIONS
Acknowledgments
This work was supported in part by the CMREF (Cardiovascular Medical Research Education Fund) to
Rajamma Mathew.

Authors’ contributions
Written the paper: Mathew R
Contributed to discussion: Dorai T

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.