Cellular Therapy for Sepsis and Lung Injury - PROJECT SUMMARY/ABSTRACT: Sepsis results from a dysregulated host response to infection leading to life-threatening organ dysfunction. It is a complex and dynamic disease process, and a leading cause of morbidity and mortality in intensive care units (ICUs). Due to the therapeutic challenges of patients with sepsis, and the fact that management remains predominantly supportive, there is an undeniable need to develop new treatment strategies for sepsis. New advances being explored include cell-based therapies. For more than 25 years my laboratory has explored the pathobiology of sepsis, and related organ injuries, including the lung. Our approach is to investigate mechanisms of disease, starting at the cellular level in vitro and translating these findings into models of disease ex vivo and in vivo. To complement our work further in sepsis, with an interest in therapy, we became interested in stem/stromal cells. My laboratory has explored the use of mesenchymal stem/stromal cells (MSCs) for therapeutic intervention in pre-clinical models of sepsis and lung injury. We investigate mechanisms responsible for the biological activity of MSCs, including paracrine actions via their conditioned medium and the impact of MSC-derived extracellular vesicles (EVs) and their cargo (miRNAs). To advance our understanding of cellular therapy for sepsis, we recently began to explore a new source of cells – placenta-derived trophoblast stem cells (TSCs). Our laboratory was the first to isolate murine (m) TSCs, using CD117 as a cell surface marker of stem/progenitor cells. Beyond paracrine actions, these cells can engraft and differentiate into parenchymal cells. We now propose to advance our investigation of TSCs harvested from human(h) term placentas. hMSCs are immune evasive, and hTSCs are immune privileged, allowing the use of both cells for allogeneic therapy. We will investigate hMSCs and hTSCs to modify the pathobiology of sepsis and provide insight into the immune response to eradicate microbes, resolve inflammation, and decrease organ injury along with promoting repair. Sepsis and organ injury, such as acute respiratory distress syndrome (ARDS), are very heterogeneous clinical processes, thus targeting a specific biological pathway is challenging. We propose that viable therapeutic cells will sense the underlying septic environment, and respond accordingly with varied paracrine actions. Plasma and immune cells from patients with sepsis ± ARDS, compared with ICU control (non-infected) patients, will allow us to explore a personalized approach using hMSCs and hTSCs. Moreover, due to differences that exist between human and mouse lungs, we propose to evaluate the actions of hMSC and hTSCs using human lung organoids and precision-cut lung slices (PSLS) as human models of lung/alveolar injury, and transcriptomic approaches to identify pathways critical for disease modification. Thus, our vision is to advance the insight into therapies for sepsis using hMSCs and hTSC, and that using human models of disease in vitro, ex vivo, and with confirmation in a pre-clinical model of pneumosepsis will provide insight into critical sepsis pathways and advance our approach to the therapy of sepsis and ARDS.
