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).