Paving the Road for Mesenchymal Stem Cell-Derived Exosome Therapy in Bronchopulmonary Dysplasia and Pulmonary Hypertension

Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung disease characterized by inflammation and arrest of alveolarization. Its common sequela, pulmonary hypertension (PH), presents with elevated pulmonary vascular resistance associated with remodeling of the pulmonary arterioles. Despite notable advancements in neonatal medicine, there is a severe lack of curative treatments to help manage the progressive nature of these diseases. Numerous studies in preclinical models of BPD and PH have demonstrated that therapies based on mesenchymal stem/stromal cells (MSCs) can resolve pulmonary inflammation and ameliorate the severity of disease. Recent evidence suggests that novel, cell-free approaches based on MSC-derived exosomes (MEx) might represent a compelling therapeutic alternative offering major advantages over treatments based on MSC transplantation. Here, we will discuss the development of MSC-based therapies, stressing the centrality of paracrine action as the actual vector of MSC therapeutic functionality, focusing on MEx. We will briefly present our current understanding of the biogenesis and secretion of MEx, and discuss potential mechanisms by which they afford such beneficial effects, including immunomodulation and restoration of homeostasis in diseased states. We will also review ongoing clinical trials using MSCs as treatment for BPD that pave the way for bringing cell-free, MEx-based therapeutics from the bench to the NICU setting.