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

Table 2

The mechanism analysis of EVs against PH.

References	Year	Disease Model	Type of EVs	Target Cell or Tissue	Molecular Mechanism	Therapeutic Effect
[88]	2018	Hypoxia	MSC-Exos	Macrophage	Inhibition of macrophage infiltration and reduced the release of inflammatory factors	Reduced hypoxic/ischemic damage
[89]	2018	BPD	MSC-Exos	Macrophage	Suppression of the proinflammatory “M1” state and augment of an anti-inflammatory “M2-like” state	Improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling
[74]	2019	Sugen/hypoxia	MSC-EVs	Macrophages	Increased the ratio of alternatively to classically activated macrophages (M2/M1)	Normalized RV pressure and reduced RV hypertrophy and muscularization of peripheral pulmonary vessels
[77]	2016	MCT	MSC-Exos	Pulmonary arterial	Increased levels of anti-inflammatory, antiproliferative miRs	Prevented any increase in RV/LV; S, WT/D ratios
[90]	2012	Hypoxia	MSC-Exos	HPAECs	Increased lung levels of miR-204 and inhibited STAT3 signaling	Exerted a pleiotropic protective effect on the lung
[79]	2019	MCTP	ASCs-Exos	HPAECs	miR-191 repressed the expression of BMPR2	Inhibited HPAECs proliferation
[91]	2017	Balloon angioplasty injury on rat carotid arteries	EVs from EC-CM	SMCs	Transferred miR-195 from ECs to SMCs	Inhibited the expression of 5-HTT in SMCs and the proliferation of SMCs.
[50]	2018	Cultured BOECs	Exos from BOECs (isolated from patients harboring BMPR2 mutations)	PASMCs	Transferred TCTP from ECs to PASMCs	TCTP overexpression induced proliferation and reduced apoptosis
[9]	2020	MCT or hypoxia	MSC-Exos	HPAECs and PASMCs	Upregulated the expression of Wnt5a	The inhibition effect on EndMT and promotion adhesion ability
[10]	2018	Hyperoxia-exposed BPD	MSC-Exos	Alveolar	Detected TSG-6 in Exos	Attenuated BPD and its associated pathologies
[76]	2018	MCT	MSC-MVs	Lung tissue	Upregulated ACE2 mRNA in the lung tissues and plasma levels of Ang-(1–7)	Exerted beneficial effects against MCT-induced PAH
[92]	2019	Hypoxia	MSC-Exos	PASMCs	Increased PASMC expression of PDH and GLUD1	Improved the mitochondrial dysfunction

ASCs: adipose-derived mesenchymal stem cells; HPAECs: human pulmonary artery endothelial cells; BMPR2; bone morphogenetic protein receptor 2; MCTP: monocrotaline pyrrole; EC-CM: endothelial cells conditional medium; SMCs: smooth muscle cells; PASMC: pulmonary artery smooth muscle cells; TCTP: translationally controlled tumor protein; BOECs: blood outgrowth endothelial cells; BPD: bronchopulmonary dysplasia; TSG-6: tumor necrosis factor alpha-stimulated gene-6; NAb: neutralizing antibody; PDH: pyruvate dehydrogenase; GLUD1: glutamate dehydrogenase 1.