The role of resident lung mesenchymal stromal cells in the pathogenesis of bronchopulmonary dysplasia (BPD).

• Applicant: Dr. Ivana Mizik, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Cell Biology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417891009

Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows ventilator and O2 therapy for acute respiratory failure, is the most common complication of prematurity and accounts for much of the long-term morbidity. BPD is characterized by impaired lung development and lacks effective therapies. Exogenous (bone marrow or umbilical cord) mesenchymal stromal cells (MSC) prevent O2-induced lung injury in newborn rodents. An apparent contradiction is the observation that premature babies are more likely to develop BPD if MSCs are present in their tracheal aspirates. Thus, in order to facilitate the clinical translation of this promising cell therapy, we will clarify the intriguing role of resident lung (L-)MSC in neonatal lung injury and repair.Hypothesis: The repair function of L MSCs is perturbed in experimental BPD and L-MSC dysfunction may contribute to the pathogenesis of BPD. Aim 1: To characterize L-MSCs in the normal developing mouse lung and determine if the function of L-MSCs is perturbed in experimental BPD. 1.1. We will isolate L-MSCs from normal mice and determine their characteristics (cell surface markers, differentiation and clonogenic potential and cytokine and extracellular matrix protein production). 1.2. We will use these same endpoints to compare L-MSCs from normal mice to mice with ventilation-induced lung injury (VILI) mimicking BPD. Mice will be exposed to LPS and mechanically ventilated for 8 hours. We will also perform RNAseq to compare the transcription of normal L-MSC compared to L-MSC isolated from mice with VILI. In addition, we will perform in vitro functional assays to compare the healing potential of L-MSCs. We will compare the effect of L-MSCs from control mice and from VILI mice on proliferation and wound healing of freshly isolated alveolar epithelial cells and proliferation and network formation on matrigel of lung endothelial cells.Aim 2: To determine if L-MSCs contribute to the pathogenesis of BPD. In vivo, we will inject normal mouse pups or pups exposed to hyperoxia (n=10/group) at P4 (onset of alveolar development) with either control L-MSCs (isolated previously from normally developing mice) or L-MSCs isolated from VILI mice and compare the effect on lung function and structure at P14. The strengths of this proposal include the novelty in exploring the role of endogenous L-MSCs, the readily availability of the animal models, well-established techniques to isolate and characterize L-MSCs, lung function and structure as well as the direct clinical implications. Indeed, the functional in vitro assays may serve as potency assays to predict the in vivo bioactivity of the cells. Furthermore, a better understanding of L-MSCs tissue specific function may contribute to develop superior exogenous MSC-based therapies. The relevance of our findings may extend to adult lung diseases characterized by alveolar damage such as emphysema and acute respiratory distress syndrome.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Bernard Thébaud, Ph.D.