3.22 Preclinical treatment with MSCs in PAH
The research about MSC therapy in PAH is much earlier than EPC therapy,
and the effect of MSC therapy is also more recognized. Huang et al.
showed that after MSC transplantation, sugen-hypoxia induced-PH (Su-Hx
PH) rats and chronic hypoxia-induced pulmonary hypertension (CHPH) rats
exhibited a significant decrease in right ventricle pressure and degree
of pulmonary artery remodeling. Masson’s trichrome staining results
showed that MSCs ameliorated the collagen deposition around the
pulmonary arterial vasculature. MSCs also attenuated the process of
endothelial-to-mesenchymal transition (EndMT) by reducing the expression
of HIF-2α(J. Huang et al., 2020). Furthermore, Huang et al. also
investigated the secretory function of MSCs by injecting MSC conditional
medium (MSC-CM) into mice, and they obtained the same trend as that
observed with cell suspension.
These results showed that the both control group and experimental groups
exhibited a high level of HIF-2α under hypoxic conditions. However, the
group that received MSC-CM treatment exhibited a faster disappearance
rate of HIF-2α, indicating that MSC-CM inhibited HIF-2α by promoting its
degradation(J. Huang et al., 2020).
Rathinasabapathy et al. found that adipose source MSCs (ASCs) and their
conditional medium can modulate numerous types of cytokines, including
significantly downregulating pro-inflammatory cytokines such as TNFα,
IL-1, and IL-6, markers of immune defense system such as toll-like
receptor 4 (TLR-4), cytokine-inducible NOS (iNOS), and markers of tissue
remodeling such as TGF-β, and upregulating the markers of
anti-inflammatory cytokines such as IL-10(Rathinasabapathy et al.,
2016). In the past decade, an increasing number of scientists has
concentrated their attention on the exosome of MSCs. Without exception,
the exosome of MSCs was also effective, as some scientists found that
the expression levels of Wnt5a, Wnt11, BMPR2, BMP4, and BMP9 increased,
but β-catenin, cyclin D1, and TGF-β1 decreased in the MSC exosome group
in vivo and in vitro. Considering that the immunogenicity of exosomes is
lower than that of a cell suspension, if we have an efficient method to
obtain sufficient exosomes, then these exosomes may constitute a more
effective treatment (Table 2).
Chen et al. transfected MSCs with the eNOS and F92A-Cav1 genes using
lentivirus vector to verify the feasibility of gene editing technology
in MSCs and increase the effect of MSCs. The results showed that the
serum NO concentration significantly increased in eNOS-MSCs, and
eNOS/F92A-Cav1-MSCs inhibited proliferation of PASMCs and improved
pulmonary hemodynamics, vascular remodeling, and short-term survival(H.
Chen et al., 2017). Cheng et al. used adenovirus to transfect MSCs with
the lethal-7a (let-7a) microRNA, so that the let-7a-MSCs would
overexpress let-7a microRNA, and the results showed that let-7a-MSCs
ameliorated MCT-induced ventricular impairment, attenuated pulmonary
vascular remodeling, and regulated PASMC proliferation and apoptosis
resistance(Cheng, Wang, Li, & He, 2017).