Mesenchymal Stem Cell-derived Extracellular Vesicles Prevent Experimental Bronchopulmonary Dysplasia Complicated By Pulmonary Hypertension

Abstract

Mesenchymal stem cell (MSC) extracellular vesicles (EVs) have beneficial effects in preclinical bronchopulmonary dysplasia and pulmonary hypertension (BPD-PH) models. The optimal source, dosing, route, and duration of effects are however unknown. The objectives of this study were to (a) compare the efficacy of GMP-grade EVs obtained from Wharton’s Jelly MSCs (WJ-MSCs) and bone marrow (BM-MSCs), (b) determine the optimal dosing and route of administration, (c) evaluate its long-term effects, and (d) determine how MSC EVs alter the lung transcriptome. Newborn rats exposed to normoxia or hyperoxia (85% O2) from postnatal day (P)1-P14 were given (a) intra-tracheal (IT) BM or WJ-MSC EVs or placebo, (b) varying doses of IT WJ-MSC EVs, or (c) IT or intravenous (IV) WJ-MSC EVs on P3. Rats were evaluated at P14 or 3 months. Early administration of IT BM-MSC or WJ-MSC EVs had similar beneficial effects on lung structure and PH in hyperoxia-exposed rats. WJ-MSC EVs however had superior effects on cardiac remodeling. Low, medium, and high dose WJ-MSC EVs had similar cardiopulmonary regenerative effects. IT and IV WJ-MSC EVs similarly improved vascular density and reduced PH in hyperoxic rats. Gene-set enrichment analysis of transcripts differentially expressed in WJ-MSC EV-treated rats showed that induced transcripts were associated with angiogenesis. Long-term studies demonstrated that a single early MSC EV dose has pulmonary vascular protective effects 3 months after administration. Together, our findings have significant translational implications as it provides critical insight into the optimal source, dosing, route, mechanisms of action, and duration of effects of MSC-EVs for BPD-PH.

Perinatal origins of bronchopulmonary dysplasia—deciphering normal and impaired lung development cell by cell

“…Human UC-MSC-derived EVs were shown to improve alveolar and vascular development, as well as lung function and RVH in hyperoxia-exposed developing mice [ 281 – 283 ]. Similar results were further observed in studies employing EVs from amniotic fluid-derived [ 284 ] and Wharton’s Jelly-derived MSCs [ 285 ]. Studies indicate that EVs exert their mostly anti-inflammatory effects by promoting an immunosuppressive CCR2-associated myeloid cell phenotype [ 283 ].…”

Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway

“…Specifically, MSC-EV administration was reported to restore endothelial cell viability, improve pulmonary arterial contractility, and mitigate extracellular matrix remodeling in models of CDH 45,46 . There is also evidence that an EV-based therapy improves lung vascular development and prevents pulmonary hypertension in experimental models of bronchopulmonary dysplasia, a neonatal lung condition that affects premature babies and is similar to pulmonary hypoplasia secondary to CDH [47][48][49][50][51] . In these studies, EV-based therapies were reported to improve lung vascular density, attenuate vascular remodeling, and prevent pulmonary hypertension [47][48][49][50][51] .…”

“…There is also evidence that an EV-based therapy improves lung vascular development and prevents pulmonary hypertension in experimental models of bronchopulmonary dysplasia, a neonatal lung condition that affects premature babies and is similar to pulmonary hypoplasia secondary to CDH [47][48][49][50][51] . In these studies, EV-based therapies were reported to improve lung vascular density, attenuate vascular remodeling, and prevent pulmonary hypertension [47][48][49][50][51] . This experience with EVs in a neonatal condition mirrors the beneficial effects demonstrated by EVbased therapy in adult preclinical models of pulmonary arterial hypertension 52,53 .…”

A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic

“…BPD therapy with MSC-EVs has been shown to reduce the effects of oxidative stress and its markers, indicating the presence of antioxidant mechanisms [ 169 , 170 ]. Tissue homeostasis in the lung is also associated with the development of an intense inflammatory response leading to fibrosis, vascular remodeling and pulmonary hypertension [ 171 , 172 ]. The first study on the protective paracrine properties of MSCs in the development of acute neonatal pulmonary hypertension showed that the fractionation of the conditioned culture medium on exosomes contributed to a reduction in lung infiltration by macrophages and inflammation, as well as a decrease in the development of pulmonary hypertension by modulating the signal transducer and activator of transcription 3 (STAT3) signaling pathway [ 173 ].…”