Novel strategies for therapeutic programming and delivery of mesenchymal stem cells to improve outcome of influenza virus-induced lung injury
Bone marrow-derived mesenchymal stem/stromal cells (MSC) have promising therapeutic potential in different forms of acute lung injury (ALI), and are now in first clinical studies. However, the molecular mechanisms underlying their injury- or pathogen-related beneficial effects within defined niches of the affected lung are poorly understood. In particular, the molecular interactions and pathways of injury sensing by MSC in viral infection of the lung are widely unknown. It is also not well defined, how MSC are recruited to sites of infection or inflammation, and whether distinct subsets of MSC hold different therapeutic potential. Therefore, a detailed analysis of the molecular interactions between virus-infected lung cells and MSC, mediating injury-specific priming and lung homing of defined MSC subsets with particular anti-viral, immunomodulatory and organ repair capacity, is envisioned in this project.
We hypothesize that understanding the cell-cell communication, the paracrine signaling pathways, and the molecular basis of injury-associated beneficial programming of MSC, will allow us to further enhance their therapeutic potential. Using established murine and human primary alveolar epithelial cell/MSC co-cultures and mouse models of IV-induced lung injury allowing tracing and flow-sorting of previously applied MSC, combined with NGS and proteomics approaches, we aim to
(i) understand the heterogeneity of MSC and their relative contribution to disease-relevant processes,
(ii) identify transcriptional changes induced in MSC in the context of IV-induced ALI, and to functionally characterize key signaling molecules mediating beneficial effects of MSC,
(iii) characterize the impact of different priming modalities on the phenotype and the therapeutic efficacy of MSC, and
(iv), improve homing of MSC to IV-injured lung tissue.
These efforts will ultimately enhance antiviral, anti-inflammatory, epithelial-protective and regenerative activities of MSC, as well as MSC accumulation within lung regions where these MSC functions are particularly needed to improve outcome of virus-induced lung injury.