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

Fig. 1

Tab.1

Fig. 2

Fig. 3

Fig. 4

Fig. 5

Tab.2

Fig. 6

Fig. 7

References 27

[1]	陈昭，吴林，蓝雪琳，等. 血管性痴呆发病机制中西医研究进展［J］. 辽宁中医药大学学报， 2022， 24（1）： 40-44.
[2]	RUNDEK T， TOLEA M， ARIKO T， et al. Vascular cognitive impairment （VCI）［J］. Neurotherapeutics， 2022， 19（1）： 68-88.
[3]	WOLTERS F J， ARFAN IKRAM M. Epidemiology of vascular dementia［J］. Arterioscler Thromb Vasc Biol， 2019， 39（8）： 1542-1549.
[4]	INOUE Y， SHUE F， BU G J， et al. Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease［J］. Mol Neurodegener， 2023， 18（1）： 46.
[5]	PATHAN N， KHAROD M K， NAWAB S， et al. Genetic determinants of vascular dementia［J］. Can J Cardiol， 2024， 40（8）： 1412-1423.
[6]	SANTOS M A O， BEZERRA L S， CORREIA C D C， et al. Neuropsychiatric symptoms in vascular dementia： epidemiologic and clinical aspects［J］. Dement Neuropsychol， 2018， 12（1）： 40-44.
[7]	WANG D P， LI B W， WANG S C， et al. Engineered inhaled nanocatalytic therapy for ischemic cerebrovascular disease by inducing autophagy of abnormal mitochondria［J］. NPJ Regen Med， 2023， 8（1）： 44.
[8]	杨超，杨佳，刘玲. 涤痰汤对血管性痴呆大鼠海马NOX2/ROS通路、GSH、HO-1表达的影响［J］. 中国老年学杂志， 2019， 39（12）： 3052-3055.
[9]	BONORA M， GIORGI C， PINTON P. Molecular mechanisms and consequences of mitochondrial permeability transition［J］. Nat Rev Mol Cell Biol， 2022， 23（4）： 266-285.
[10]	HE Y Y， HE T T， LI H P， et al. Deciphering mitochondrial dysfunction： Pathophysiological mechanisms in vascular cognitive impairment［J］. Biomed Pharmacother， 2024， 174： 116428.
[11]	HE S Z， WANG Q Q， CHEN L K， et al. miR-100a-5p-enriched exosomes derived from mesenchymal stem cells enhance the anti-oxidant effect in a Parkinson’s disease model via regulation of Nox4/ROS/Nrf2 signaling［J］. J Transl Med， 2023， 21（1）： 747.
[12]	TURANO E， SCAMBI I， VIRLA F， et al. Extracellular vesicles from mesenchymal stem cells： towards novel therapeutic strategies for neurodegenerative diseases［J］. Int J Mol Sci， 2023， 24（3）： 2917.
[13]	PALANISAMY C P， PEI J J， ALUGOJU P， et al. New strategies of neurodegenerative disease treatment with extracellular vesicles （EVs） derived from mesenchymal stem cells （MSCs）［J］. Theranostics， 2023， 13（12）： 4138-4165.
[14]	TELI P， KALE V， VAIDYA A. Mesenchymal stromal cells-derived secretome protects Neuro-2a cells from oxidative stress-induced loss of neurogenesis［J］. Exp Neurol， 2022， 354： 114107.
[15]	JIANG X H， LI H F， CHEN M L， et al. Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling［J］. Neural Regen Res， 2023， 18（6）： 1293-1299.
[16]	RADWAN R R， MOHAMED H A. Mechanistic approach of the therapeutic potential of mesenchymal stem cells on brain damage in irradiated mice： emphasis on anti-inflammatory and anti-apoptotic effects［J］. Int J Radiat Biol， 2023， 99（9）： 1463-1472.
[17]	ZHUO Y， LI W S， LU W， et al. TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson’s disease models and patients［J］. Mil Med Res， 2024， 11（1）： 48.
[18]	LINH T T D， HSIEH Y C， HUANG L K， et al. Clinical trials of new drugs for vascular cognitive impairment and vascular dementia［J］. Int J Mol Sci， 2022， 23（19）： 11067.
[19]	TIAN Z M， JI X M， LIU J. Neuroinflammation in vascular cognitive impairment and dementia： current evidence， advances， and prospects［J］. Int J Mol Sci， 2022， 23（11）： 6224.
[20]	JOMOVA K， RAPTOVA R， ALOMAR S Y， et al. Reactive oxygen species， toxicity， oxidative stress， and antioxidants： chronic diseases and aging［J］. Arch Toxicol， 2023， 97（10）： 2499-2574.
[21]	LYU Y J， MENG Z P， HU Y Y， et al. Mechanisms of mitophagy and oxidative stress in cerebral ischemia-reperfusion， vascular dementia， and Alzheimer’s disease［J］. Front Mol Neurosci， 2024， 17： 1394932.
[22]	HE F， RU X L， WEN T. NRF2， a transcription factor for stress response and beyond［J］. Int J Mol Sci， 2020， 21（13）： 4777.
[23]	YANG S X， XIE Z P， PEI T T， et al. Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ_1-42-induced Alzheimer’s disease mice and glutamate-injured HT22 cells［J］. Chin Med， 2022， 17（1）： 82.
[24]	黄健，曹诗杰，安红伟. 自噬与血管性痴呆关系研究进展［J］. 中华老年心脑血管病杂志， 2022， 24（2）： 219-221.
[25]	WEI P H， JIA M， KONG X Y， et al. Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice［J］. Stem Cell Res Ther， 2023， 14（1）： 263.
[26]	KAISAR M A， VILLALBA H， PRASAD S， et al. Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury： Is Metformin a viable countermeasure？［J］. Redox Biol， 2017， 13： 353-362.
[27]	GEORGE M， THARAKAN M， CULBERSON J， et al. Role of Nrf2 in aging， Alzheimer’s and other neurodegenerative diseases［J］. Ageing Res Rev， 2022， 82： 101756.

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

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 9

References 27

Related Articles 15

Metrics

Comments

Recommended 0

[1]	Han LIN,Qiuyan YANG,Jieyue ZHONG,Bolun CHEN,Wangxia TONG. Improvement effect of cordycepin on ferroptosis in HepG2 cells induced by RSL3 and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2025, 51(3): 576-589.
[2]	Jing DENG,Xuan WANG,Changyu SHI,Siqi YANG,Qinling ZOU,Ming JIN. Effect of securinine on proliferation and apoptosis of human colon cancer SW620 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2025, 51(2): 307-316.
[3]	Meng QU,Rui HUANG,Xinda JU,Yuxin LIU,Jichen XIA,Jiaxin HUANG,Chunyan YU,Zhiheng DONG. Ameliorative effect of ginsenoside Rh1 on kidney injury in diabetic mice through activation of Nrf2/HO-1 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2024, 50(6): 1565-1571.
[4]	Qiao WANG,Ziling ZENG,Xing WANG,Ning MA,Zhibin WANG,Guofeng XU,Xiefang YUAN,Xiaoyun WANG,Yuejiao LI,Hongmei TANG,Yun ZHANG. Effect of Aspergillus fumigatus on DNA damage and IL-33 expression in human bronchial epithelial cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(5): 1205-1216.
[5]	Yuexin LIU,Yongwei LAI,Yanchun WANG,Bo XU,Qian LU,Ying AN,Kuang REN,Hongyan FAN. Improvement effect of total flavonoids of Sophora flavescens on oxidative stress induced by lead acetate in leydig cells in mice and its in effect on Keap1/Nrf2 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2024, 50(2): 320-325.
[6]	Donghong CAI,Qing LI,Lingling KE,Huiya ZHONG,Qilong JIANG,Han ZHANG,Yafang SONG. Expression of mitophagy and apoptosis related genes in peripheral blood mononuclear cells of patients with myasthenia gravis and its clinical diagnosis value [J]. Journal of Jilin University(Medicine Edition), 2024, 50(2): 481-488.
[7]	Hongmei TANG,Yuejiao LI,Xing WANG,Zhibin WANG,Xiefang YUAN,Xiaoyun WANG. Effect of Jiegeng Yuanshen Tang on airway inflammation and mucus secretion in allergic asthmatic mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(1): 10-17.
[8]	Xiaoshuang HE,Lina XU,Mei CUI,Wenyan XIN. Inhibitory effect of BMSCs over-expressing FOXO1 on pulmonary eosinophil infiltration and airway remodeling in asthmatic mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2023, 49(5): 1192-1201.
[9]	Hao ZHANG,Cuizhu WANG,Huimin HUANGFU,Xinwei ZHANG,Yidi ZHANG,Yanmin ZHOU. Effect of 20(S)-protopanaxadiol on osteogensis differentiation of bone marrow mesenchymal stem cells in rats and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2023, 49(4): 867-874.
[10]	Naixu SHI,Miao HAO,Tianfu ZHANG,Kelin ZHAO,Ziyan HUANG,Chunyan LI,Xiaofeng WANG. Inhibitory effect of baicalein on proliferation of human tongue squamous cell carcinoma CAL27 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2023, 49(4): 985-993.
[11]	Bo HUANG,Jie DING,Hongrong GUO,Hongjuan WANG,Jianqun XU,Quan ZHENG. Effects of HIF-1α/ROS on apoptosis and invasion of lung cancer A549 cells under hypoxia and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2023, 49(3): 682-690.
[12]	Xuechun DU,Baosheng LI,Shuwei QIAO,Yanzhen OU,Zhen LI,Weiyan MENG. Effect of Porphyromonas gingivalis-LPS on expression levels of ferroptosis-related factors in macrophages [J]. Journal of Jilin University(Medicine Edition), 2022, 48(5): 1148-1155.
[13]	Wentao WANG,Xuguang MI,Yang ZHOU,Wenxing PU,Jiaxu GAO,Meng JING,Fankai MENG. Effect of autophagy induced by exosomes derived from bone marrow mesenchymal stem cells on survival of SH-SY5Y cells inhibited by MPP⁺ and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2022, 48(3): 606-614.
[14]	Haixin QU,Erwei YUAN,Weiping GUO,Yajing ZHANG,Wenxia MA,Dan WU. Improvement effect of luteolin on acute respiratory distress syndrome by inhibiting ROS/TXNIP/NLRP3 signaling pathway activation in mice [J]. Journal of Jilin University(Medicine Edition), 2022, 48(3): 676-683.
[15]	Yinong LIU,Qiang ZHANG,Li XU. Improvement effect of atorvastatin on vascular endothelial dysfunction induced by Ox-LDL/β2GPⅠ/anti-β2GPⅠ complex and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2022, 48(2): 317-323.