中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (2): 440-446.doi: 10.4103/1673-5374.379049

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

纤维蛋白-凝血酶微囊包封人诱导神经干细胞移植脊髓损伤大鼠:调节微环境促进功能恢复

  

  • 出版日期:2024-02-15 发布日期:2023-08-30
  • 基金资助:
    干细胞与转化国家重点项目;国家自然科学基金;北京市自然科学基金;北京市人才基金;北京市 "十三五 "高校高层次教师支持项目;北京市卫生健康委员会基金;北京市百千万人才工程;英国皇家学会-牛顿高级研究金;中国国家青年科学基金

Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Sumei Liu1, Baoguo Liu1, Qian Li1, Tianqi Zheng1, Bochao Liu1, Mo Li1, Zhiguo Chen1, 2, 3, *   

  1. 1Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; 2Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China; 3Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, China
  • Online:2024-02-15 Published:2023-08-30
  • Contact: Zhiguo Chen, PhD, chenzhiguo@gmail.com.
  • Supported by:
    This work was supported by the Stem Cell and Translation National Key Project, No. 2016YFA0101403 (to ZC), the National Natural Science Foundation of China, Nos. 82171250 and 81973351 (to ZC), the Natural Science Foundation of Beijing, No. 5142005 (to ZC), Beijing Talents Foundation, No. 2017000021223TD03 (to ZC), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan, No. CIT & TCD20180333 (to ZC), Beijing Municipal Health Commission Fund, No. PXM2020_026283_000005 (to ZC), Beijing One Hundred, Thousand, and Ten Thousand Talents Fund, No. 2018A03 (to ZC), and the Royal Society-Newton Advanced Fellowship, No. NA150482 (to ZC), the National Natural Science Foundation of China for Young Scientists, No. 31900740 (to SL).

摘要:

目前研究主要集中在观察细胞移植对病变脊髓后功能恢复的影响,而关于移植的细胞和/或生物材料调节脊髓损伤微环境作用的研究则较少被关注。实验首次将人类外周单核细胞重编程为诱导神经干细胞,然后将纤维蛋白-凝血酶微囊包封的人诱导神经干细胞移植到大鼠脊髓病变部位。BBB评分、电生理功能和免疫荧光/组织学分析结果显示,移植促进了脊髓损伤大鼠运动和电生理功能的恢复,减少了病变体积,并促进了病变核心处轴突神经丝的表达。对移植物和神经龛成分的分析显示,尽管移植物只存活了相对较短的时间(最多15天),但它仍能对微环境产生重要影响。诱导神经干细胞复合人纤维蛋白可减少浸润的免疫细胞数量,使小胶质细胞趋于向M2表型转化,并改变病变部位的细胞因子表达谱。表明纤维蛋白-凝血酶微囊包封的人诱导神经干细胞移植可调节脊髓损伤后的微环境,促进脊髓损伤后的功能恢复。

https://orcid.org/0000-0003-1508-510X (Zhiguo Chen)

Abstract: Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord, with the expectation that differentiated neurons facilitate recovery. Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment. Here, we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury. Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells, and/or thrombin plus fibrinogen, were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model. Basso, Beattie and Bresnahan score, electrophysiological function, and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function, reduces lesion volume, and promotes axonal neurofilament expression at the lesion core. Examination of the graft and niche components revealed that although the graft only survived for a relatively short period (up to 15 days), it still had a crucial impact on the microenvironment. Altogether, induced neural stem cells and human fibrin reduced the number of infiltrated immune cells, biased microglia towards a regenerative M2 phenotype, and changed the cytokine expression profile at the lesion site. Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions, which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Key words: biomaterial, fibrinogen, functional recovery, induced neural stem cell transplantation, microenvironment, microglia, spinal cord injury, thrombin