Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies

Table 1

The effects of MSC-EVs against experimental PH.

References	Year	animals or cells	model	EV source	Therapeutic strategy	Impact indicators	Effects mechanisms
[73]	2021	Rats	MCT	UCMSCs-Exos	Tail vein injection once daily	Reduced RVSP and RVHI	Suppressed the pulmonary vascular remodeling and the EndMT process.
[9]	2020	Rats	MCT or hypoxia -induced cell damage model	UCMSCs-Exos	Tail vein injection once daily or added into the cells cultured medium	Attenuated RV hypertrophy and PASMC proliferation	Suppressed the pulmonary vascular remodeling and EndMT process or inhibited hypoxia-induced PAEC apoptosis
[74]	2020	Rats	Sugen/Hypoxia	MSC-EVs	Tail vein injection once daily for 3 Days	Reduced RV hypertrophy	Supressed muscularization of peripheral pulmonary vessels
[75]	2014	Rats	MCT	BMMSC-MVs	Injection for 2 weeks	Reduced RV hypertrophy and pulmonary arteriole AI and TI	Reduced pulmonary arteriole remodeling
[76]	2018	Rats	MCT	BMMSC-MVs	Tail vein injection every 2 days until 5 weeks	Relieved RV hypertrophy index, pulmonary vessel wall TI, pulmonary vessel lumen AI, the inflammation score, and the collagen fiber volume fraction	Shifted the balance from ACE-Ang-II-AT1R axis toward the ACE2-Ang-(1–7)-mas axis
[77]	2016	Mice	MCT	mMSC-Exos	Tail vein injection once daily for 3 days	Prevented any increase in RV/LV + S, pulmonary arterial WT/D	Reversed pulmonary vascular remodeling
[78]	2021	Rats	SuHx	MSC-EVs	Tail vein injection once weekly for five weeks	Reduced RVSP, RV/LV + S, and muscularization index	Reduced pulmonary vascular remodeling
[79]	2019	Rats	MCTP	ASCs-Exos	Injected for four weeks	Improved proliferation of MCTP-treated HPAECs	Regulation of BMPR2
[80]	2020	Rodents	Nitrofen administration	MSC-EVs	Intravenous infusion upon birth.	Bolstered structural aspects of the PAECM and mitigated pathological disorganization	Rapid inhibition of ECM-remodeling enzymes (LOX and MMP-9)
[81]	2020	Newborn mice	HYRX	MEx	Injected via the superficial temporal vein	Decreased pulmonary fibrosis and vascular muscularization	Ameliorated lung injury, improved alveolar simplification, pulmonary fibrosis, vascular remodeling and blood vessel loss

EVs: extracellular vesicles; Exos: exosomes; MCT: monocrotaline; MSCs: mesenchymal stem cells; UCMSCs: umbilical cord mesenchymal stem cells; BMMSCs: bone marrow mesenchymal stem cells; mMSCs: murine MSCs; ASCs: adipose mesenchymal stem cells; RVSP: the right ventricular systolic pressure; RVHI: right ventricular hypertrophy index; EndMT: endothelial-mesenchymal transition; RV: right ventricular; PASMC: pulmonary arterial smooth muscle cells; AI: area index; TI: thickness index; mMSCs: murine MSCs; RV/LV + S: right-to-left ventricle + septum wet weight ratio; WT/D: wall thickness-to-diamete; SuHx: rats treated with sugen 5416 and exposed to three weeks of hypoxia; MCTP: monocrotaline pyrrole; CDH: congenital diaphragmatic hernia; PA: pulmonary artery; ECM: the extracellular matrix; HYRX: hyperoxia; MEx: MSC-derived small extracellular vesicles.