Stem cell-derived extracellular vesicles: a potential intervention for Bronchopulmonary Dysplasia

Abstract

Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among extreme preterm infants. The pathogenesis of BPD is multifactorial, with inflammation playing a central role. There is strong evidence that stem cell therapy reduces inflammatory changes and restores normal lung morphology in animal models of hyperoxia-induced lung injury. These therapeutic effects occur without significant engraftment of the stem cells in the host lung, suggesting more of a paracrine mechanism mediated by their secretome. In addition, there are multiple concerns with stem cell therapy which may be alleviated by administering only the effective vesicles instead of the cells themselves. Extracellular vesicles (EVs) are cell-derived components secreted by most eukaryotic cells. They can deliver their bioactive cargo (mRNAs, microRNAs, proteins, growth factors) to recipient cells, which makes them a potential therapeutic vehicle in many diseases, including BPD. The following review will highlight recent studies that investigate the effectiveness of EVs derived from stem cells in preventing or repairing injury in the preterm lung, and the potential mechanisms of action that have been proposed. Current limitations will also be discussed as well as suggestions for advancing the field and easing the transition towards clinical translation in evolving or established BPD. IMPACT: Extracellular vesicles (EVs) derived from stem cells are a potential intervention for neonatal lung diseases. Their use might alleviate the safety concerns associated with stem cell therapy. This review highlights recent studies that investigate the effectiveness of stem cell-derived EVs in preclinical models of bronchopulmonary dysplasia. It adds to the existing literature by elaborating on the challenges associated with EV research. It also provides suggestions to advance the field and ease the transition towards clinical applications. Optimizing EV research could ultimately improve the quality of life of extreme preterm infants born at vulnerable stages of lung development.

Fig. 1. Stages of lung development and the evolving pathophysiology of BPD.

With the increased survival of extreme preterm infants and the advances in neonatal care, the definition and pathophysiology of BPD have changed over time. Histologic characteristics of “old BPD” and “new BPD” are presented. Multiple intrinsic, antenatal, and postnatal risk factors contribute nowadays to the development of the disease [Created with BioRender].

Fig. 2. Major historical timepoints in EV research.

Key points in the history of EV research are illustrated in this timeline [Created with BioRender].

Fig. 3. Common EV isolation techniques, categorized according to their yield and specificity.

The ideal goal of obtaining a purified EV population with both high yield and high specificity remains unrealistic with the currently available techniques. DGC density gradient centrifugation, dUC differential or sequential ultracentrifugation (low-to-high speed), MW molecular weight, SEC size-exclusion chromatography, UC ultracentrifugation, UF ultrafiltration, TTF tangential flow filtration (also known as cross-flow filtration, as opposed to the term “filtration” used to refer to the traditional dead-end filtration where fluid flows perpendicular to the membrane). [Created with BioRender].