Study on the therapeutic potential of induced neural stem cells for Alzheimer's disease in mice

• Published in: Biological research 2024-11, Vol.57 (1), p.89-12, Article 89
• Main Authors: Ji, Qiongqiong, Lv, Yuanhao, Hu, Bei, Su, Yue, Shaikh, Imran Ibrahim, Zhu, Xu
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - therapy; Alzheimer's disease; Alzheimer’s disease (AD); Animals; Antibodies; Astrocytes; Brain; Cell Differentiation; Cell survival; Cell therapy; Cognitive ability; Disease Models, Animal; Diseases; Divalproex; Embryo fibroblasts; Fibroblasts; Fibroblasts - transplantation; Genetic engineering; Glial cells; Growth factors; Health aspects; Hippocampus - cytology; Induced neural stem cells (iNSCs); Mice; Mice, Transgenic; Mouse embryonic fibroblasts (MEFs); Nestin; Neural stem cells; Neural Stem Cells - transplantation; Neurodegenerative diseases; Neuronal-glial interactions; Neurons; Neurons - transplantation; Oligodendrocytes; Penicillin; Presenilin 1; Recovery of function; Sox2; SOXB1 Transcription Factors - metabolism; Spinal cord; Stem cells; Transgenic mice; Transplantation; Transplantation treatment; Valproic acid; Valproic acid (VPA); Valproic Acid - therapeutic use
• ISSN: 0717-6287; 0716-9760; 0717-6287
• DOI: 10.1186/s40659-024-00568-0

Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer's disease.