骨髓来源的间充质干细胞移植通过ROS/Nrf2信号对血管性痴呆大鼠线粒体自噬的影响及其机制

doi:10.13481/j.1671-587X.20250306

Abstract

Abstract:

Objective To discuss the effects of bone marrow-derived mesenchymal stem cells （BMSCs） transplantation on mitophagy in the vascular dementia （VaD） rats through reactive oxygen species （ROS）/nuclear factor erythroid 2-related factor 2 （Nrf2） signaling， and to clarify its mechanism. Methods Forty-five male adult SD rats were randomly divided into sham operation group， model group， unloaded group， BMSCs group， and MSCs+ML385 （Nrf2 inhibitor） group （combination group）， and there were 9 rats in each group. After intraperitoneal anesthesia， the VaD models were established in all groups except sham operation group. Morris water maze test was used to detect the learning and memory abilities of the rats in various groups； HE staining was used to observe the histopathological morphology of brain tissue of the rats in various groups； Nissl staining was used to observe the changes of Nissl bodies in hippocampus region of brain tissue of the rats in various groups； transmission electron microscope was used to observe the ultrastructure of hippocampus region of the rats in various groups； fluorescence probe method was used to detect the ROS levels in hippocampus neurons in various groups； Western blotting method was used to detect the expression levels of Nrf2， heme oxygenase-1 （HO-1）， PTEN-induced putative kinase 1 （PINK1）， parkin RBR E3 ubiquitin protein ligase （Parkin）， Beclin-1， ubiquitin-binding protein p62 （P62）， and microtubule-associated protein 1A/1B-light chain 3 （LC3-Ⅱ/LC3-Ⅰ） ratio in brain tissue of the rats in various groups. Results The Morris water maze results showed that compared with sham operation group， the escape latency of the rats in model group was significantly increased （P<0.01）， while the number of crossing time and residence time were significantly decreased （P<0.01）. Compared with model group， the escape latency of the rats in BMSCs group was significantly decreased （P<0.01）， while the number of crossing time and residence time were significantly increased （P<0.01）. Compared with BMSCs group， the escape latency of the rats in combination group was significantly increased （P<0.01）， while the number of crossing time and residence time were significantly decreased （P<0.01）. The HE staining results showed that hippocampus neurons of the rats in sham operation group were normal in quantity and morphology， with uniform staining and clear structure. Compared with sham operation group， the hippocampus tissue of the rats in model group showed sparse arrangement， disordered structure， reduced neuronal quantity， varied morphology， uneven staining， nuclear pyknosis， and partial neuronal necrosis. Compared with model group， the neuronal damage of the rats in hippocampus regio in BMSCs group was alleviated， with restored morphology and improved neuronal loss. Compared with BMSCs group， the neurons of the rats in hippocampus region in combination group showed irregular morphology， disordered structure， unclear cell boundaries， uneven staining， and nuclear pyknosis. The Nissl staining results showed that the hippocampal neurons in sham operation group were tightly arranged with intact morphology， obvious nucleoli， and abundant darkly stained Nissl bodies. Compared with sham operation group， the neurons in hippocampus region of the rats in model group showed pyknosis， vacuolization， and sparse Nissl bodies. Compared with model group， the BMSCs group showed reduced neuronal pyknosis， relatively intact morphology， and increased Nissl bodies. Compared with BMSCs group， the combination group showed neuronal pyknosis， loss of morphological integrity， and fragmented Nissl bodies. The transmission electron microscope results showed that mitochondria in sham operation group exhibited oval shape with intact double-membrane structure and cristae. Compared with sham operation group， the mitochondria in model group showed swelling， disrupted membranes， broken cristae， and numerous autophagosomes. Compared with model group， the BMSCs group showed improved mitochondrial structure and reduced autophagosomes. Compared with BMSCs group， the combination group showed swollen mitochondria， disrupted membranes， broken cristae， and visible autophagosomes. The fluorescence probe results showed that compared with sham operation group， the ROS levels in the hippocampus neurons in brain tissue of the rats in model group were significantly increased （P<0.01）； compared with model group， the ROS levels in hippocampus neurons in brain tissue of the rats in BMSCs group were significantly decreased （P<0.01）； compared with BMSCs group， the ROS levels in hippocampus neurons in brain tissue of the rats in combination group were significantly increased （P<0.01）. The Western blotting results showed that compared with sham operation group， the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in model group were significantly decreased （P<0.01）； compared with model group， the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in BMSCs group were significantly increased （P<0.01）； compared with BMSCs group， the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in combination group were significantly decreased （P<0.01）； compared with sham operation group， the expression levels of Parkin， PINK1， and Beclin-1 proteins， and LC3-Ⅱ/LC3-Ⅰ ratio of the rats in model group were significantly increased （P<0.01）， while the expression level of P62 protein was significantly decreased （P<0.01）； compared with model group， the expression levels of Parkin， PINK1， and Beclin-1 proteins， as well as the LC3-Ⅱ/LC3-Ⅰ ratio， of the rats in BMSCs group were significantly decreased （P<0.01）， while the expression level of P62 protein was significantly increased （P<0.01）； compared with BMSCs group， the expression levels of Parkin， PINK1， and Beclin-1 proteins， as well as the LC3-Ⅱ/LC3-Ⅰ ratio， of the rats in combination group were significantly increased （P<0.01）， while the expression level of P62 protein was significantly decreased （P<0.01）. Conclusion BMSCs can alleviate the hippocampal neuronal pathological changes and improve cognitive function in the VaD rats， and its mechanism may be related to the regulation of ROS/Nrf2 signaling pathway to inhibit mitophagy.

Key words: Vascular dementia, Bone marrow mesenchymal stem cells, Nuclear factor erythroid 2-related factor 2, Reactive oxygen species, Mitophagy

CLC Number:

R743.9

Lieqian SUN,Mengyu GU,Jie YANG,Kaiyi WANG,Gaoshuai GUO,Hongbo ZHANG,Siyi ZHANG,Tanglong WANG,Zhiwei YANG,Yanni HE,Chao YANG. Effect of bone marrow-derived mesenchymal stem cell transplantation on mitochondrial autophagy in rats with vascular dementia through ROS/Nrf2 signaling and its mechanism[J].Journal of Jilin University(Medicine Edition), 2025, 51(3): 610-620.

Figures/Tables 9

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References 27

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Group	Escape latency（t/s）	Number of crossing time	Residence time in platform quadrant（t/s）
Sham operation	23.61±2.40	11.67±2.35	58.29±2.72
Model	37.60±2.93^*	4.00±2.06^*	32.87±2.92^*
Unloaded	37.71±2.29	4.22±1.79	32.67±2.94
BMSCs	26.64±2.40^△	10.44±2.51^△	51.30±4.20^△
Combination	36.24±3.17^#	5.33±1.50^#	38.83±3.35^#

Group	Level of ROS
Sham operation	30.89±2.96
Model	87.77±2.06^*
Unloaded	84.10±2.69
BMSCs	42.87±3.35^△
Combination	69.17±4.18^#

Effect of bone marrow-derived mesenchymal stem cell transplantation on mitochondrial autophagy in rats with vascular dementia through ROS/Nrf2 signaling and its mechanism

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