Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-05-13 DOI:10.1038/s41368-024-00300-4
Wei Xiong, Ye Liu, Heng Zhou, Junyi Li, Shuili Jing, Cailei Jiang, Mei Li, Yan He, Qingsong Ye
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Abstract

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

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人牙髓干细胞通过 AKT-GSK3β-Nrf2 通路减轻阿尔茨海默病的神经病理变化和认知能力下降
人们日益认识到,氧化应激是阿尔茨海默病(AD)病理生理学的一个主要因素,尤其是在疾病的早期阶段。干细胞移植的多重优势使其成为许多神经退行性疾病的迷人治疗策略。我们在此证明,在体外AD模型中,人牙髓干细胞(hDPSCs)介导了氧化应激的改善和神经恢复效应,在调节高反应性小胶质细胞的极化和受损神经元的恢复中发挥了关键作用。重要的是,这些治疗效果在10个月大的3xTg-AD小鼠单次移植hDPSCs后得到了体现,接受治疗的小鼠在认知功能和神经病理学特征方面都有显著改善。从机理上讲,hDPSCs的抗氧化和神经保护作用以及认知能力的提高至少部分是由Nrf2核积累和下游抗氧化酶的表达通过激活AKT-GSK3β-Nrf2信号通路介导的。总之,我们的研究结果证实了hDPSCs在体外和体内AD模型中重塑神经病理微环境的神经保护能力,这可能是阿尔茨海默病的一个巨大的潜在治疗候选方案。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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