Alleviation of mutant TDP-43-mediated neuropathology by inducible stem cells in monkeys
Abnormal cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43) is a common pathological feature of TDP-43 proteinopathies. Since non-human primate models can better recapitulate this neuropathology than rodents, we used a monkey model to evaluate the therapeutic potential of stem cells for TDP-43-mediated neuropathology. We established a cynomolgus monkey model by expressing mutant TDP-43 (M337V) in the monkey striatum through AAV injection. This model exhibited motor dysfunction and abnormal cytoplasmic TDP-43 accumulation. Using multi-gene modified stem cells (NILB-hiPSCs) that can be induced to differentiate <i>in vivo</i> with doxycycline treatment, we found that transplanted NILB-hiPSCs improved the limb movements of the TDP-43-injected monkeys, differentiated into mature neurons, and were integrated with neural circuit activity in the monkey brain. Furthermore, NILB-hiPSC therapy reduced reactive gliosis and diminished the abnormal cytoplasmic localization of mutant TDP-43. These results highlight the potential of <i>in vivo</i> inducible stem cells for the treatment of TDP-43 proteinopathies.
Authors
- Kai‐Wei Liao (ORCID: https://orcid.org/0000-0003-3842-416X)
- Sen Yan (ORCID: https://orcid.org/0000-0003-4889-1570)
- Caijuan Li (ORCID: https://orcid.org/0000-0001-6754-8829)
- Zheng Xiao (ORCID: https://orcid.org/0000-0003-4519-0074)
- Yizhi Chen (ORCID: https://orcid.org/0000-0003-0555-3918)
- Jianhao Wu
- Yingqi Lin (ORCID: https://orcid.org/0000-0003-1700-8722)
- Liangxue Lai
- Chaoran Ren (ORCID: https://orcid.org/0000-0002-6147-8644)
- Libing Zhou (ORCID: https://orcid.org/0000-0002-8975-5228)
- Huiyi Wei
- Xichen Song
- Song Lin (ORCID: https://orcid.org/0000-0003-0489-9239)
- Lu Huang (ORCID: https://orcid.org/0000-0002-4552-1403)
- Kwok‐Fai So (ORCID: https://orcid.org/0000-0003-4039-4246)
- Peng Yin (ORCID: https://orcid.org/0000-0002-4811-6956)
- Min Chen (ORCID: https://orcid.org/0000-0002-9790-7244)
- Lu Wang (ORCID: https://orcid.org/0000-0003-4559-3607)
- Wei Wang (ORCID: https://orcid.org/0000-0001-8157-1435)
- Yang Yang (ORCID: https://orcid.org/0000-0003-3973-2738)
- Shihua Li (ORCID: https://orcid.org/0000-0003-1775-6536)
- Jiaxi Wu (ORCID: https://orcid.org/0000-0002-6976-4784)
- Xiao‐Jiang Li (ORCID: https://orcid.org/0000-0002-9370-8838)
- Jiale Gao (ORCID: https://orcid.org/0000-0002-6992-7387)
- Hao Xu (ORCID: https://orcid.org/0000-0002-8311-506X)
- Chunhui Huang
- Wenguang Xie
- Zhen Dai (ORCID: https://orcid.org/0000-0003-3468-954X)
- Huiming Yang
- Jiawei Li (ORCID: https://orcid.org/0000-0001-9957-8192)
- Zhonghai Huang (ORCID: https://orcid.org/0000-0001-8249-6297)
- Zhuchi Tu
Institutions
- First Affiliated Hospital of Jinan University (CN)
Publication Details
- Journal
- International Journal of Biological Sciences
- Published
- 2025-11-20
- DOI
- https://doi.org/10.7150/ijbs.122557
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00