HBEGF/EGFR pathway activation by hUC-MSCs improves cognitive outcomes in anti-NMDAR encephalitis

  • Mol Ther. 2025 Oct 16:S1525-0016(25)00861-5. doi: 10.1016/j.ymthe.2025.10.040.
Jingfang Lin  1 ,  Bingjun Zhang  2 ,  Huiming Xu  3 ,  Xinghua Zhong  1 ,  Xuejia Li  4 ,  Yanna Song  5 ,  Xi Wang  3 ,  Yu Peng  1 ,  Haotian Wu  3 ,  Haijia Chen  4 ,  Jiaohua Jiang  4 ,  Qiyi Chen  4 ,  Yuanyuan Wang  6 ,  Changyong Tang  7 ,  Honghao Wang  8
Affiliations
  • 1. Department of Neurology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province 510180, China.
  • 2. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China; Department of Neurology, Health Management Center, Zhaoqing Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Zhaoqing, Guangdong Province 526000, China.
  • 3. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China.
  • 4. Guangzhou SALIAI Stem Cell Science and Technology Co., Ltd., Guangdong Saliai Stem Cell Research Institute, Guangzhou, Guangdong Province, China.
  • 5. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China; Department of Neurology, Qingdao Municipal Hospital, Qingdao, Shandong Province 266000, China.
  • 6. Department of Neurology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province 510180, China. Electronic address: [email protected].
  • 7. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China. Electronic address: [email protected].
  • 8. Department of Neurology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province 510180, China. Electronic address: [email protected].
PMID: 41108076 DOI: 10.1016/j.ymthe.2025.10.040
Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder that impairs cognitive function. In this study, we investigated the impact of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on cognitive recovery in anti-NMDAR encephalitis. Our findings demonstrate that heparin-binding epidermal growth factor-like growth factor (HBEGF), a key functional factor secreted by hUC-MSCs, plays a pivotal role in ameliorating cognitive dysfunction. We elucidated that the HBEGF/epidermal growth factor receptor (EGFR) signaling pathway contributes to the enhancement of cognitive function following hUC-MSC exposure. Importantly, we employed a novel exosome-based intracellular therapeutic protein delivery technology-the mMaple3-mediated protein loading and release from exosomes (MAPLEX) system-for targeted HBEGF delivery. This approach facilitated a controlled, light-induced release of HBEGF from the exosomal membrane. Collectively, these findings support the involvement of HBEGF in mediating cognitive improvement in anti-NMDAR encephalitis induced by hUC-MSCs. Additionally, the MAPLEX system emerges as an effective delivery platform for HBEGF, potentially opening new avenues for the treatment of anti-NMDAR encephalitis.

Keywords
NMDAR; NMDAR reduction; anti-N-methyl-D-aspartate receptor encephalitis; cognitive impairment; epidermal growth factor receptor; heparin-binding epidermal growth factor-like growth factor.
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