Pediatr Pulmonol. 2020 Jun 22. doi: 10.1002/ppul.24914. [Epub ahead of print] https://pmlegacy.ncbi.nlm.nih.gov/pubmed/32568428

Extracellular vesicles influence the pulmonary arterial extracellular matrix in congenital diaphragmatic hernia.

Monroe MN¹, Zhaorigetu S², Gupta VS², Jin D², Givan KD¹, Curlyo AL¹, Olson SD², Cox CS Jr², Segura A³, Maximilian Buja L³, Jane Grande-Allen K¹, Harting MT².

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Abstract

OBJECTIVE:

Abnormal pulmonary vasculature directly affects the development and progression of congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH). Though overarching structural and cellular changes in CDH-affected pulmonary arteries have been documented, the precise role of the extracellular matrix (ECM) in pulmonary artery (PA) pathophysiology remains undefined. Here, we quantify the structural, compositional, and mechanical CDH-induced changes in the main and distal PA ECM and investigate the efficacy of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a therapy to ameliorate pathological vascular ECM changes.

METHODS:

Pregnant Sprague-Dawley rodents were administered nitrofen to induce CDH-affected pulmonary vasculature in the offspring. A portion of CDH-affected pups were treated with intravenous infusion of MSC-EVs (1×10¹⁰ /ml) upon birth. A suite of histological, mechanical, and transmission electronic microscopic analyses were utilized to characterize the PA ECM.

RESULTS:

The CDH model main PA presented significantly altered characteristics – including greater vessel thickness, greater lysyl oxidase (LOX) expression, and a relatively lower ultimate tensile strength of 13.6 MPa compared to control tissue (25.1 MPa), suggesting that CDH incurs ECM structural disorganization. MSC-EV treatment demonstrated the potential to reverse CDH-related changes, particularly through rapid inhibition of ECM remodeling enzymes (LOX and MMP-9). Additionally, MSC-EV treatment bolstered structural aspects of the PA ECM and mitigated pathological disorganization as exhibited by increased medial wall thickness and stiffness that, while not significantly altered, trends away from CDH-affected tissue.

CONCLUSIONS:

These data demonstrate notable ECM remodeling in the CDH pulmonary vasculature, along with the capacity of MSC-EVs to attenuate pathological ECM remodeling, identifying MSC-EVs as a potentially efficacious therapeutic for CDH-associated pulmonary hypertension. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

congenital diaphragmatic hernia; exosomes; extracellular matrix; extracellular vesicles; mesenchymal stem cells; mesenchymal stromal cells; microvesicles; pulmonary hypertensionPMID: 32568428 DOI: 10.1002/ppul.24914