中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (9): 1959-1960.doi: 10.4103/1673-5374.335145

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

受损大脑干细胞治疗后的神经元回路重建

  

  • 出版日期:2022-09-15 发布日期:2022-03-05

Neuronal circuitry reconstruction after stem cell therapy in damaged brain

Daniel Tornero*   

  1. Department of Biomedical Sciences, Institute of Neuroscience and Production and Validation Center of Advanced Therapies (Creatio), University of Barcelona; August Pi I Sunyer Biomedical Research Institute (IDIBAPS); Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
  • Online:2022-09-15 Published:2022-03-05
  • Contact: Daniel Tornero, PhD,daniel.tornero@ub.edu.
  • Supported by:
    The present work was supported by Ministerio de Ciencia e Innovación (Spain), under project No. PID2020-118120RB-I00; European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813851; and European Union’s FET-Open program grant agreement, No. 9648877 (to DT).

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摘要： 神经元移植有助于大脑功能恢复
评估细胞疗法对脑组织功能恢复的贡献最确定和最优雅的策略涉及使用光遗传学或化学遗传学（即使用 DREADD）来沉默移植神经元。将表达光门控氯泵氯化物视紫红质的人胚胎干细胞衍生的中脑多巴胺能神经元移植到帕金森小鼠模型的纹状体中。移植的动物从病变引起的帕金森运动缺陷中恢复过来，并且光诱导的移植物活动沉默可逆地重新引入了小鼠的单侧行为。最新研究表明，人诱导多能干细胞衍生的皮层神经元移植到影响体感和运动皮层的缺血性病变附近，促进了动物的功能恢复。移植后 6 个月，表达视紫红质移植神经元的光遗传学沉默导致大鼠双侧损伤（圆柱体试验）。移植神经元的正确定位促进了特定传入和传出突触连接的产生，从而重建预先存在的回路，特别是经胼胝体交流。这可以解释在大鼠卒中模型中移植神经元沉默后观察到的双侧损伤。如使用注射了表达盐细菌视紫红质的慢病毒的完整大鼠所示，来自体感和相邻运动区域的皮层神经元的沉默导致双侧损伤，这应该是抑制时的预期结果功能性整合在大脑该区域的神经元活动。这两项研究证明了移植的神经元衍生活性在动物模型的长期功能恢复中的贡献，为临床应用的发展开辟了新的途径。
来自西班牙巴塞罗那大学的Daniel Tornero认为，新形成神经元的身份是在大脑发育的早期阶段确定的，并且是由发育信号的精确时空调节决定的。这些发育信号在多大程度上仍然存在于成人大脑中尚不清楚，必须进一步探索。 重要的是，移植部位微环境，包括细胞因子的类型和免疫反应的细胞成分，会从脑损伤的急性阶段变为慢性阶段，不同程度地促进移植细胞的成熟和整合。总之，新的神经元可以在受伤后取代死细胞，这是脑功能最佳、长期恢复的关键。未来的研究应着眼于了解干细胞疗法对脑损伤修复的有益作用背后的机制。尽管这种方法存在一些明显的局限性，但基于干细胞治疗的临床应用正在成为现实。 基础研究和临床研究之间的相互合作应该有助于克服临床实践中基于干细胞治疗的当前局限性和未来挑战。
文章在《中国神经再生研究（英文版）》杂志2022年9 月 9 期发表。

Abstract: Transplantation of neuronal precursors derived from human pluripotent stem cells is a promising therapy for the treatment of neurological disorders associated with neuronal loss, such us neurodegenerative diseases, brain trauma and stroke. The functional integration of grafted neurons differentiated from stem cells into the host injured neuronal circuitry has been a major challenge in cell therapy strategies for brain repair (Palma-Tortosa et al., 2021). Even though other cell types or mechanisms may provide modest clinical improvements, neuronal replacement and reconstruction of the damaged area are crucial for an optimal and long-term recovery. This process entails three important aspects (Figure 1): (1) the generation of specific neuronal subtypes representative of the damaged brain area, (2) the formation of functional afferent synaptic connections from the host brain to the grafted neurons, and (3) the establishment of functional efferent synaptic contacts from grafted cells to specific areas of the host brain. We previously showed that human skin-derived neural precursors, transplanted into the somatosensory cortex of rats after ischemic stroke, develop a pattern of afferent synaptic connections similar to endogenous neurons located in this area of the brain (Tornero et al., 2017), and form efferent connections with neurons of proper host brain structures (Palma-Tortosa et al., 2020). The ability of grafted cells to functionally integrate in the damaged host brain circuitry has been further demonstrated by other recent studies using animal models (Palma-Tortosa et al., 2021). Interestingly, also transplantation of human cortical neurons onto ex vivo organotypic cultures of adult human cortex proved the establishment of afferent and efferent synapses between host and grafted cells (Grønning Hansen et al., 2020). However, the mechanisms behind functional recovery and integration of new neurons into the brain network still present some unknown aspects that will be discussed in this article (Figure 1).