中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (8): 1785-1794.doi: 10.4103/1673-5374.332151

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

人脐带间充质干细胞鞘内给药治疗亚急性不完全性脊髓损伤的剂量优化

  

  • 出版日期:2022-08-15 发布日期:2022-01-22
  • 基金资助:
    国家重点研发计划(2017YFA0105401)、国家自然科学基金(31671420和81602482)和广东省骨关节重点实验室的资助

Dose optimization of intrathecal administration of human umbilical cord mesenchymal stem cells for the treatment of subacute incomplete spinal cord injury

Ting-Ting Cao1, #, Huan Chen1, #, Mao Pang2, 3, 4, #, Si-Si Xu1, Hui-Quan Wen5, Bin Liu2, 3, 4, *, Li-Min Rong2, 3, 4, *, Mang-Mang Li1, *   

  1. 1Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China; 2Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China; 3Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China; 4Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China; 5Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
  • Online:2022-08-15 Published:2022-01-22
  • Contact: Mang-Mang Li, PhD, mangmangli@smu.edu.cn; Bin Liu, MD, liubin6@mail.sysu.edu.cn; Li-Min Rong, PhD, ronglm@mail.sysu.edu.cn .
  • Supported by:
    This work was supported by the National Key Research and Development Program of China, No. 2017YFA0105401 (to LMR), the National Natural Science Foundation of China, Nos. 31671420 and 81602482 (to MML) and a grant from the Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases.

摘要:

人脐带间充质干细胞(hUC-MSCs)由于其低免疫原性和相较于其他间充质干细胞来源更容易获得的优势,可作为治疗SCI的一个潜力候选干细胞;然而,由于人脐带间充质干细胞的治疗SCI的效果可能受许多因素,如细胞来源、植入时间、给药途径和相关有效细胞剂量的影响,目前还未形成针对hUC-MSCs 治疗SCI 的有效临床转化方案。作者既往的工作已经在大鼠模型中评估了4×106 hUC-MSCs/kg通过鞘内移植治疗亚急性SCI的安全性和疗效。为了寻找更准确的剂量范围用于临床转化,实验比较了3种剂量的hUC-MSCs,即低(0.25×106个细胞/kg)、中剂量(1×106个细胞/kg)和高剂量(4×106个细胞/kg)鞘内移植对亚急性SCI大鼠模型的干预效果。行为学、解剖病理学、磁共振-弥散张量成像(MRI-DTI)、生物素化葡聚糖胺(BDA)追踪、电生理学以及离子通道和神经递质受体的mRNA水平量化结果显示,中剂量hUC-MSCs与高剂量一样有效,且可部分恢复γ-氨基丁酸A型(GABAA)受体的表达,这也表明GABAA受体是治疗损伤脊髓休眠中转途径的可能候选靶点。总之,1×106个hUC-MSCs/kg是鞘内移植治疗亚急性SCI的优化剂量。

https://orcid.org/0000-0002-4182-6509 (Mang-Mang Li); https://orcid.org/0000-0003-0373-7393 (Li-Min Rong);
https://orcid.org/0000-0003-1882-318X (Bin Liu)

Abstract: Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate for spinal cord injury (SCI) repair owing to their advantages of low immunogenicity and easy accessibility over other MSC sources. However, modest clinical efficacy hampered the progression of these cells to clinical translation. This discrepancy may be due to many variables, such as cell source, timing of implantation, route of administration, and relevant efficacious cell dose, which are critical factors that affect the efficacy of treatment of patients with SCI. Previously, we have evaluated the safety and efficacy of 4 × 106 hUC-MSCs/kg in the treatment of subacute SCI by intrathecal implantation in rat models. To search for a more accurate dose range for clinical translation, we compared the effects of three different doses of hUC-MSCs – low (0.25 × 106 cells/kg), medium (1 × 106 cells/kg) and high (4 × 106 cells/kg) – on subacute SCI repair through an elaborate combination of behavioral analyses, anatomical analyses, magnetic resonance imaging-diffusion tensor imaging (MRI-DTI), biotinylated dextran amine (BDA) tracing, electrophysiology, and quantification of mRNA levels of ion channels and neurotransmitter receptors. Our study demonstrated that the medium dose, but not the low dose, is as efficient as the high dose in producing the desired therapeutic outcomes. Furthermore, partial restoration of the γ-aminobutyric acid type A (GABAA) receptor expression by the effective doses indicates that GABAA receptors are possible candidates for therapeutic targeting of dormant relay pathways in injured spinal cord. Overall, this study revealed that intrathecal implantation of 1 × 106 hUC-MSCs/kg is an alternative approach for treating subacute SCI.

Key words: effective dose, human umbilical cord mesenchymal stem cells, intrathecal implantation, ion channels, neurotransmitter receptors, spinal cord injury, subacute spinal cord injury, γ-aminobutyric acid type A (GABAA) receptors