The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat

Abstract

Background Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis. Methods We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens. Results Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study. Conclusions In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway

“…Using a rat cecal slurry model, Hwang et al . ( 30 ) have reported that transplantation of mitochondria isolated from rat L6 cells can improve survival rate, mitigate mitochondrial dysfunction, and attenuate hyperinflammation. Our study also demonstrated that intravenous administration of mitochondria isolated from human UC-MSCs (PN-101) and those from human platelets could improve survival rates of LPS-challenged mice ( Fig.…”

Effects of Glucocorticoid Therapy on Sepsis Depend Both on the Dose of Steroids and on the Severity and Phase of the Animal Sepsis Model

“…We used a body weight-adjusted polymicrobial IAI sepsis model according to our previous study [ 15 , 16 ]. In brief, donor rats were anesthetized with an intramuscular injection of Zoletil (50 mg/kg) and xylazine (10 mg/kg).…”

Mitochondrial Transplantation: Is It a Feasible Therapy to Prevent the Cardiorenal Side Effects of Cisplatin?

“…Once the mitochondria to be transplanted are obtained, they can be incorporated into the tissues with experimental techniques that depend on the site and the type of injury. In in vivo studies, mitochondria have been transplanted through different routes; for example, during administration in the blood circulation (systemic transplantation), mitochondria have been injected through coronary arteries, renal arteries, and the tail vein [109,110,126,127]. Mitochondria have also been transplanted directly to the tissue (in situ transplantation) in the renal capsule, or directly into the myocardium [45,87,89,100,111].…”