中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (6): 1376-1386.doi: 10.4103/1673-5374.327357

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

淀粉样前体蛋白肽APP96-110与人间充质干细胞联合应用可增强对损伤脊髓的修复作用

  

  • 出版日期:2022-06-15 发布日期:2021-12-17

Effects of amyloid precursor protein peptide APP96-110, alone or with human mesenchymal stromal cells, on recovery after spinal cord injury

Stuart I. Hodgetts1, 2, *, Sarah J. Lovett1, D. Baron-Heeris1, A. Fogliani1, Marian Sturm3, C. Van den Heuvel4, Alan R. Harvey1, 2   

  1. 1School of Human Sciences, The University of Western Australia (UWA), Perth, WA, Australia; 2Perron Institute for Neurological and Translational Science, Perth, WA, Australia; 3Cell and Tissue Therapies WA (CTTWA), Royal Perth Hospital, Perth, WA, Australia; 4Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia 
  • Online:2022-06-15 Published:2021-12-17
  • Contact: Stuart I. Hodgetts, PhD, stuart.hodgetts@uwa.edu.au.
  • Supported by:
    This work was supported by the Neurotrauma Research Program of Western Australia.

摘要:

研究显示,淀粉样前体蛋白肽APP96-110对脑卒中和脑创伤有神经保护作用,鉴于此,实验评估了APP96-110或该肽的突变形式mAPP96-110对成年裸鼠胸段脊髓中度挫伤性后的影响。(1)在脊髓损伤后30min,大鼠单次尾静脉注射APP96-110或mAPP96-110, 8周后评估其功能状况。部分大鼠在伤后1周还接受了有活力或无活力的人间充质干细胞(hMSCs)移植到脊髓病变部位,以评估静脉内APP96-110递送与人间充质干细胞治疗相结合的干预效果; (2)在脊髓损伤后8周分析大鼠脊髓人间充质干细胞生存力,囊肿大小,轴突再生,神经胶质反应性和巨噬细胞活化; (3)Ladderwalk或Ratwalk测试的感觉运动功能分析结果显示,APP96-110结合与不结合人间充质干细胞治疗均未能使功能结局得到持续改善。单独的mAPP96-110,以及APP96-110结合有活力和无活力的人间充质干细胞明显缩小了损伤脊髓囊肿大小,联合治疗也明显增加了βIII微管蛋白、胶质纤维酸性蛋白和层粘连蛋白的表达,并降低了组织中ED1的表达; (4)这项研究表明,脊髓损伤后静脉内递送APP96-110肽可对脊髓损伤起到一定程度的神经保护作用,当与人间充质干细胞移植联合使用时,这种保护作用可能会增强。

https://orcid.org/0000-0002-3318-0410 (Stuart I. Hodgetts)

Abstract: Delivery of a peptide (APP96-110), derived from amyloid precursor protein (APP), has been shown to elicit neuroprotective effects following cerebral stroke and traumatic brain injury. In this study, the effect of APP96-110 or a mutant version of this peptide (mAPP96-110) was assessed following moderate (200 kdyn, (2 N)) thoracic contusive spinal cord injury (SCI) in adult Nude rats. Animals received a single tail vein injection of APP96-110 or mAPP96-110 at 30 minutes post-SCI and were then assessed for functional improvements over the next 8 weeks. A cohort of animals also received transplants of either viable or non-viable human mesenchymal stromal cells (hMSCs) into the SC lesion site at one week post-injury to assess the effect of combining intravenous APP96-110 delivery with hMSC treatment. Rats were perfused 8 weeks post-SCI and longitudinal sections of spinal cord analyzed for a number of factors including hMSC viability, cyst size, axonal regrowth, glial reactivity and macrophage activation. Analysis of sensorimotor function revealed occasional significant differences between groups using Ladderwalk or Ratwalk tests, however there were no consistent improvements in functional outcome after any of the treatments. mAPP96-110 alone, and APP96-110 in combination with both viable and non-viable hMSCs significantly reduced cyst size compared to SCI alone. Combined treatments with donor hMSCs also significantly increased βIII tubulin+, glial fibrillary acidic protein (GFAP+) and laminin+ expression, and decreased ED1+ expression in tissues. This preliminary study demonstrates that intravenous delivery of APP96-110 peptide has selective, modest neuroprotective effects following SCI, which may be enhanced when combined with hMSC transplantation. However, the effects are less pronounced and less consistent compared to the protective morphological and cognitive impact that this same peptide has on neuronal survival and behaviour after stroke and traumatic brain injury. Thus while the efficacy of a particular therapeutic approach in one CNS injury model may provide justification for its use in other neurotrauma models, similar outcomes may not necessarily occur and more targeted approaches suited to location and severity are required. All animal experiments were approved by The University of Western Australia Animal Ethics Committee (RA3/100/1460) on April 12, 2016.

Key words: amyloid precursor protein, cell transplantation, combination, contusion, functional recovery, mesenchymal stromal cells, neuroprotection, regeneration, spinal cord injury, tissue sparing

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