Hypoxic preconditioned mesenchymal stem cells ameliorate rat brain injury after cardiopulmonary resuscitation by suppressing neuronal pyroptosis

Xiahong Tang; Jun Ke; Falu Chen; Qingming Lin; Yan You; Nan Zheng; Zheng Gong; Xu Han; Yangping Zhuang; Feng Chen

doi:10.1111/jcmm.17782

Hypoxic preconditioned mesenchymal stem cells ameliorate rat brain injury after cardiopulmonary resuscitation by suppressing neuronal pyroptosis

J Cell Mol Med. 2023 Jul;27(13):1836-1858. doi: 10.1111/jcmm.17782. Epub 2023 May 29.

Authors

Xiahong Tang¹, Jun Ke^{1

2

3}, Falu Chen^{1

2

3}, Qingming Lin^{1

2

3}, Yan You⁴, Nan Zheng^{1

2

3}, Zheng Gong^{1

2

3}, Xu Han^{1

2

3}, Yangping Zhuang^{1

2

3}, Feng Chen^{1

2

3}

Affiliations

¹ Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.
² Department of Emergency, Fujian Provincial Hospital, Fuzhou, China.
³ Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, China.
⁴ The Second Department of Intensive Care Unit, Fujian Provincial Hospital South Branch, Fuzhou, China.

Abstract

Cardiac arrest (CA) can result in cerebral ischaemia-reperfusion injury and poor neurological outcomes. While bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have protective effects in brain ischaemic disease, their efficacy can be reduced by the poor oxygen environment. In this study, we investigated the neuroprotective effects of hypoxic preconditioned BMSCs (HP-BMSCs) and normoxic BMSCs (N-BMSCs) in a cardiac arrest rat model by examining their ability to ameliorate cell pyroptosis. The mechanism underlying the process was also explored. Cardiac arrest was induced in rats for 8 min and surviving rats received 1 × 10⁶ normoxic/hypoxic BMSCs or PBS via intracerebroventricular (ICV) transplantation. Neurological function of rats was evaluated using neurological deficit scores (NDSs) and examined for brain pathology. Serum S100B and neuron-specific enolase (NSE) levels and cortical proinflammatory cytokines were measured to evaluate brain injury. Pyroptosis-related proteins in the cortex after cardiopulmonary resuscitation (CPR) were measured using western blotting and immunofluorescent staining. Transplanted BMSCs were tracked using bioluminescence imaging. Results showed significantly better neurological function and neuropathological damage after transplantation with HP-BMSCs. In addition, HP-BMSCs reduced levels of pyroptosis-related proteins in the rat cortex after CPR and significantly reduced levels of biomarkers for brain injury. Mechanistically, HP-BMSCs alleviated brain injury by reducing the expressions of HMGB1, TLR4, NF-κB p65, p38 MAPK and JNK in the cortex. Our study demonstrated that hypoxic preconditioning could enhance the efficacy of BMSCs in alleviating post-resuscitation cortical pyroptosis. This effect may be related to the regulation of the HMGB1/TLR4/NF-κB, MAPK signalling pathways.

Keywords: HMGB1/TLR4/NF-κB; MAPK; bone marrow-derived mesenchymal stem cells; cardiopulmonary resuscitation; hypoxic preconditioning; pyroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries*
Cardiopulmonary Resuscitation* / methods
HMGB1 Protein*
Heart Arrest* / therapy
Hypoxia / pathology
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells* / metabolism
NF-kappa B
Pyroptosis
Rats
Rats, Sprague-Dawley
Toll-Like Receptor 4

Substances

HMGB1 Protein
NF-kappa B
Toll-Like Receptor 4