The Study on the Regulation of Th Cells by Mesenchymal Stem Cells Through the JAK-STAT Signaling Pathway to Protect Naturally Aged Sepsis Model Rats.

Lu Wang,Rui Yuan,Feihu Zhou,Hongjun Kang,Mengmeng Yang,Zihui Deng,Zhirong Qian,Yun Li,Yan Zhao,Yan Sun,Yuyan Liu

doi:10.3389/fimmu.2022.820685

Abstract

Sepsis is the leading cause of death among patients, especially elderly patients, in intensive care units worldwide. In this study, we established a sepsis model using naturally aged rats and injected 5×106 umbilical cord-derived MSCs via the tail vein. Each group of rats was analyzed for survival, examined for biochemical parameters, stained for organ histology, and analyzed for the Th cell subpopulation ratio and inflammatory cytokine levels by flow cytometry. Western blotting was performed to detect the activity of the JAK-STAT signaling pathway. We designed the vitro experiments to confirm the regulatory role of MSCs, and verified the possible mechanism using JAK/STAT inhibitors. It was revealed from the experiments that the 72 h survival rate of sepsis rats treated with MSCs was significantly increased, organ damage and inflammatory infiltration were reduced, the levels of organ damage indicators were decreased, the ratios of Th1/Th2 and Th17/Treg in peripheral blood and spleen were significantly decreased, the levels of pro-inflammatory cytokines such as IL-6 were decreased, the levels of anti-inflammatory cytokines such as IL-10 were increased, and the levels of STAT1 and STAT3 phosphorylation were reduced. These results were validated in in vitro experiments. Therefore, this study confirms that MSCs can control the inflammatory response induced by sepsis by regulating Th cells and inflammatory factors, and that this leads to the reduction of tissue damage, protection of organ functions and ultimately the improvement of survival in aged sepsis model rats. Inhibition of the JAK-STAT signaling pathway was surmised that it may be an important mechanism for their action.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1] and is the leading cause of death for intensive care unit (ICU) patients, especially among the elderly
The results indicated that Mesenchymal stem cells (MSCs) derived from the umbilical cord could improve the overall status and 72 h survival of aged rats with sepsis and protect vital organ functions and ameliorate histopathological damages caused by sepsis
The applied in vivo and in vitro experiments confirmed that MSCs could inhibit the systemic inflammatory response, regulate the Th1/Th2 and Th17/Treg ratios and inflammatory cytokine levels in aged rats with sepsis, and the modulation of the JAK-STAT signaling pathway may be one of the mechanisms of action

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1] and is the leading cause of death for intensive care unit (ICU) patients, especially among the elderly. There are 30 million cases of sepsis each year with a mortality rate of 30-40% [2, 3], and more than 60% of the deceased are elderly people over 65 years of age [4]. A combination of anti-infective, anti-shock and supportive therapy has reduced the high mortality from sepsis, but the severity of it has increased year by year [5]. MSCs have been found to reduce the systemic inflammatory response, decrease the level of organ damage [10], and improve the survival of sepsis model animals [11]

Methods

Results

Conclusion