Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation
US National Library of Medicine
National Institutes of Health
Gareth R. Willis,1,2 Angeles Fernandez-Gonzalez,1,2 Jamie Anastas,1,3 Sally H. Vitali,2,4 Xianlan Liu,1 Maria Ericsson,3 April Kwong,1 S. Alex Mitsialis,1,2,* and Stella Kourembanas1,2,*
Rationale: Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos).
Objectives: To assess efficacy of MSC-exo treatment in a preclinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action.
Methods: Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX; 75% O2), treated with exosomes on Postnatal Day (PN) 4 and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, -14, or -42 for assessment of pulmonary parameters.
Measurements and Main Results: HYRX-exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements after MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC-exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory “M1” state and augmenting an antiinflammatory “M2-like” state, both in vitro and in vivo.
Conclusions: MSC-exo treatment blunts HYRX-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX-induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC-exo mechanism of action is associated with modulation of lung macrophage phenotype.
In conclusion, we purified and carefully characterized exosomes derived from human WJMSCs, BMSCs, and HDF-exos, and demonstrated a robust therapeutic effect in a BPD model that is specific to exosomes of MSC origin. Importantly, we demonstrate, for the first time, that purified MSC-exos are the major paracrine antiinflammatory and therapeutic mediators of MSC action in the hyperoxic lung. MSC-exos act, at least in part, through modulation of the lung macrophage phenotype, suppressing lung inflammation and immune responses to favor proper organ development. Given the recognized pleiotropic effects of MSC-exos (41), other prematurity-associated pathologies, including neurological injury, could, in the very near future, be the targets of exosome-based therapies.