The Role of Mesenchymal Stromal Cells in the Treatment of Bronchopulmonary Dysplasia: A Multi-Prong Approach for a Heterogeneous Disease

Abstract

Acute lung injury can be a devastating ailment leading to death in patients of all ages. In preterm neonates, lung injury is unique and unlike what is seen in pediatric and adult populations. The physiology behind the acute lung injury endured in developing lungs and the chronicity of harmful stimuli vastly distinguish how bronchopulmonary dysplasia (BPD), the most common complication of prematurity, settles in as a chronic lung disease with lifetime sequelae. Despite being recognized for over 50 years, BPD continues to puzzle the world of neonatology with a shifting phenotype that parallels improvement in neonatal care. The improved understanding of BPD's far-reaching and long-term consequences on the lung and other organs highlights the need to find effective interventions, making it a priority of neonatal research. In this review, we provide an overview of BPD and its associated consequences. Then, we examine the biological premises for mesenchymal stromal cells as a promising therapy, reviewing current translational efforts, challenges, and future directions toward bringing mesenchymal stromal cell therapy to BPD patients.

FIGURE 1

Timeline of the evolution of BPD and respiratory care, highlighting the currently aging preterm population from each era, displaying both acute and long‐term consequences of BPD. Schematic timeline presenting the evolution of BPD through its diagnostic definitions and phenotypes in relation to the change in respiratory care over the years. Note that the schematic only presents prominent definitions and changes in management. Definitions have been reviewed extensively elsewhere (Thébaud et al. ; Wu et al. ; Ibrahim and Bhandari 2018). It is not meant to be an exhaustive representation of BPD definitions reported nor of the various changes in management in neonatology. Aging BPD is shown in relation to the changes in respiratory care during their era, highlighting that most reports of long‐term consequences of BPD currently published are a representation of the “old BPD” phenotype, with yet an undefined long‐term progression of the “new” BPD phenotype during most of adulthood. The estimated longest follow‐up reported for patients with BPD was last described as 53 years old (Bui et al. 2022) but could theoretically be as old as 65 years of age. Estimated healthcare resources utilization is also featured (Lapcharoensap et al. ; Van Katwyk et al. 2020). Short‐term (left) and long‐term (right) co‐morbidities associated with BPD. ↓, reduce; ↑, increase; Δ, change; ANCS, antenatal corticosteroid; Approx., approximative; BPD, bronchopulmonary dysplasia; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; HRU, health resource utilization; IMV, invasive mechanical ventilation; INSURE, INtubate‐SURfactant‐Extubate; IT, intratracheal; IUGR, intra‐uterine growth restriction; Max, maximum; MIST, minimally invasive surfactant administration; NDI, neurodevelopmental impairment; NEC, necrotizing enterocolitis; NICHD, National Institute of Child Health Disease; NIH, National Institute of Health; O₂, oxygen; pHTN, pulmonary hypertension; PN, post‐natal; Prob, problem; QoL, quality of life; RCT, randomized clinical trial; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; RV, right ventricle; w, week; Y, year. PREMILOC, COIN, SUPPORT, CAP refer to short names of well‐known trials in the field of neonatology. Created in BioRender. Deguise, M. (2025) https://BioRender.com/onk2zj1 (Adaptations of numerous BioRender (2025) templates: Human Ages Timeline, Lugano, G ‐ Congenital Diaphragmatic Hernia, Delrose, N. Cancer‐Associated Comorbidities).

FIGURE 2

The various components contributing to the development and severity of BPD. Schematic representation of selected identified (not exhaustive) contributors or risk factors contributing to the development of BPD divided in four categories (Intra‐uterine factors, predisposing factors, post‐natal insults, other insults). BPD, bronchopulmonary dysplasia; IMV, invasive mechanical ventilation; IUGR, intra‐uterine growth restriction; O₂, oxygen; NEC, necrotizing enterocolitis; PPROM, prolonged premature rupture of membrane. Created in Biorender. Deguise, M. (2025) https://BioRender.com/swwb7j7 (modified from Biorender (2025) Gut‐brain axis regulators template).

FIGURE 3

MSC mechanisms in the context of BPD pathogenic processes. A depiction of major pathways involved in BPD pathogenesis is featured at the top of the figure while MSCs counter actions are featured at the bottom of the figure. More details concerning each box are present in the body of the manuscript. ↓, reduce; ↑, increase; BPD, bronchopulmonary dysplasia; macro., macrophage; metab, metabolism; NEC, necrotizing enterocolitis; prod: production. Created in BioRender. Deguise M. (2025) https://BioRender.com/kqik256 (modified from BioRender (2025) Acute Respiratory Distress Syndrome template).

FIGURE 4

Current MSC cell therapy development pipeline with an overview of completed clinical trials for BPD. The number in the circle represents the number of trials that have been completed. The incomplete circle represents the current stage of development. The total number of patients in each phase is depicted below the table of clinical trials progress. The general purpose of each phase is described in the bottom strip with complementary pictograms. Note that MSCs from other sources may be in pre‐clinical development but have not been used in clinical trials with published results. They are not represented in this figure for the sake of clarity and simplification. MoA: mechanism of action. Created in BioRender. Deguise, M. (2025) https://BioRender.com/4pe8df6.