Embryonic-Derived Myb- Macrophages Enhance Bacterial Clearance and Improve Survival in Rat Sepsis
Mirjana Jerkic1, Michael L Litvack2, Stéphane Gagnon1
1Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael's, University of Toronto, Toronto, ON M5B 1T8, Canada.
Abstract:
Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb- "peritoneal-like" macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large "peritoneal-like" macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.
Insights
Embryonic-derived large peritoneal-like macrophages (Ed-LPM) show promise in treating abdominal sepsis. This macrophage therapy improved survival rates and reduced bacterial load, offering a potential new strategy for sepsis treatment.
Area of Science:
- Immunology
- Regenerative Medicine
- Sepsis Research
Background:
- Peritoneal resident macrophages are crucial for fighting sepsis within the peritoneal cavity.
- Abdominal fecal sepsis presents a significant clinical challenge with high mortality.
- Current sepsis treatments, including antibiotics like Meropenem, have limitations.
Purpose of the Study:
- To investigate the efficacy of transplanting embryonic-derived large peritoneal-like macrophages (Ed-LPM) in attenuating abdominal fecal sepsis.
- To explore the mechanisms by which Ed-LPM influence host immune responses during sepsis.
- To assess the potential of Ed-LPM as a cell-based therapy for sepsis.
Main Methods:
- Directed differentiation of rodent pluripotent stem cells (PSCs) to generate Ed-LPM.
- Preclinical in vivo studies using a rodent model of abdominal fecal sepsis.
- Ex vivo analysis of Ed-LPM effects on immune cell function, including phagocytosis, ROS production, efferocytosis, and apoptosis.
Main Results:
- Ed-LPM transplantation significantly reduced sepsis severity by decreasing bacterial load in multiple organs (liver, spleen, lungs).
- Animal survival improved by approximately 30% with Ed-LPM therapy, comparable to Meropenem treatment.
- Ed-LPM enhanced peritoneal macrophage phagocytosis, increased ROS production, and promoted neutrophil clearance via apoptosis and efferocytosis, restoring immune homeostasis.
Conclusions:
- Ed-LPM therapy effectively reduces systemic sepsis severity and bacterial burden, improving survival rates.
- The mechanism involves enhanced bacterial phagocytosis and killing by peritoneal macrophages and clearance of neutrophils.
- Macrophage-based cell therapy represents a promising strategy for addressing sepsis.
