中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (10): 4978-4988.doi: 10.4103/NRR.NRR-D-25-01014

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

调节无细胞神经同种移植物的再生微环境可促进神经再生

  

  • 出版日期:2026-10-15 发布日期:2026-06-15

Modulation of the regenerative microenvironment within acellular nerve allografts using tacrolimus improves nerve regeneration.

Jesús A. Acevedo Cintrón, Jonathon Blake Schofield, Daniel A. Hunter, Pranay Singh, Alexa M. Negrón Morales, Lauren Schellhardt, Susan E. Mackinnon, Matthew D. Wood*   

  1. Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
  • Online:2026-10-15 Published:2026-06-15
  • Contact: Matthew D. Wood, PhD, woodmd@wustl.edu.
  • Supported by:
    This work was supported in part by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award number R01 NS115960 (to MDW) and F31 NS130990 (JAAC) to Washington University.

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摘要：

无细胞神经同种移植物（ANAs）已被用作重建神经缺损的替代方案。然而，与短段移植物（<3cm）相比，长段移植物（>3 cm）的再生与恢复效果较差。为探究长段移植物再生受限的原因，实验通过比较短段（2 cm）与长段（4 cm）移植物的转录谱，重点分析其微环境差异。在使用短/长无细胞神经同种移植物修复Lewis大鼠坐骨神经后，发现长无细胞神经同种移植物近端及中远端移植物区域呈现代谢与免疫通路上调、再生过程下调的特征，与短无细胞神经同种移植物形成对比。基于此，实验采用他克莫司（FK506）调节长无细胞神经同种移植物的再生与免疫微环境。组织形态计量学与肌力分析表明，FK506可增加长型无细胞神经同种移植物中的轴突数量并改善运动功能恢复。FK506处理组长型无细胞神经同种移植物中远端移植物区域的转录组分析显示：再生通路上调而免疫过程下调，尤其与T细胞活性相关。此外，FK506改变了长轴索神经损伤区域巨噬细胞与施万细胞的数量。转录组分析表明FK506上调Spp1（骨桥蛋白）表达，该蛋白可促进损伤后运动神经元再生。培养施万细胞实验证实FK506可增强Spp1的mRNA表达。本研究揭示长段异体神经移植物内存在退行性与免疫性微环境，并证明FK506能调节该微环境以促进长段移植物的再生。


https://orcid.org/0000-0001-8132-6827 (Matthew D. Wood)

关键词: 无细胞神经移植物, 免疫抑制, 巨噬细胞, 微环境, 神经缺损, 骨桥蛋白（SPP1）, 周围神经再生, 施万细胞, 他克莫司（FK506）, 转录组分析（RNA-Seq）

Abstract:

Acellular nerve allografts have been used as an alternative to reconstruct nerve gaps. However, regeneration and recovery using long acellular nerve allografts (> 3 cm) is poor in comparison to short acellular nerve allografts (< 3 cm). To understand why long acellular nerve allografts have limited regeneration, we focused on identifying differences in the microenvironment of short (2 cm) and long (4 cm) acellular nerve allografts by comparing the transcriptional profile of these acellular nerve allografts. After repairing the sciatic nerve of Lewis rats using either short or long acellular nerve allografts, we found that the proximal and mid-distal graft regions of long acellular nerve allografts are characterized by an upregulation of metabolic and immune pathways and downregulation of regenerative processes in comparison to the short acellular nerve allografts. Based on these results, we modulated the regenerative and immune microenvironment of long acellular nerve allografts using tacrolimus (FK506). Histomorphometric and muscle force analysis revealed that FK506 increases the number of axons and improves recovery of motor function across long acellular nerve allografts. Transcriptome analysis of the mid-distal graft region of long acellular nerve allografts from animals treated with FK506 revealed upregulation of regenerative pathways and downregulation of immune processes, specifically related to T cell activity. Additionally, FK506 altered the number of macrophages and Schwann cells in the long acellular nerve allografts. From the transcriptome analysis, we identified FK506 upregulates expression of Spp1 (osteopontin) which promotes regeneration of motor neurons after injury. Experiments on cultured Schwann cells revealed that FK506 increases mRNA expression of Spp1. Our data show the development of a degenerative and immune microenvironment within long acellular nerve allografts and demonstrate that FK506 can modulate this microenvironment to improve nerve regeneration across these long acellular nerve allografts.

Key words: acellular nerve allograft, immunosuppression, macrophages, microenvironment, nerve gap, osteopontin (SPP1), peripheral nerve regeneration, Schwann cells, tacrolimus (FK506), transcriptome analysis