人脑类器官移植促进卒中模型动物组织修复和功能重建的实验研究

Stroke is a major cause of acquired disability in adults. However there is no pharmacological therapy available for promoting recovery, as there is no specific target for tissue repair and functional rebulding in the recovery period after stroke. Various interventions such as stem cells transplation and rehabilitation training are currently being explored to enhance neuroplasticity, and thereby to improve neuronal defect behaviors to a certain extent. Because it is difficult to reconstruct the tissue structure in the infarct area, the therapeutic effects of these interventions are limited. Here we will culture three-dimensional (3D) cell tissue─human brain organoids in vitro through human pluripotent stem cell (hPSCs) directional differentiation. We will use matrigel as a biological material to support the 3D structure of brain organoids, and transplant the human brain organoids into the infarct area of SCID mice subjected to photothrombotic stroke. Moreover, we will determine whether environmental enrichment exposure facilitates the brain organoids to survive, differentiate into target neurons and correctly integrate into the host neural circuit. And more importantly, whether the brain organoids transplatation reconstructs the tissue structure in the infarct area and substantially eliminates neuronal defect behaviors of stroke mice. Our research will reveal a novel technique for trying to cure stoke.

卒中是成年人最主要的后天致残原因。然而，迄今尚无针对卒中恢复期的组织修复和功能重建的特异靶标，因此缺乏有效的恢复期治疗药物。在探索中的干细胞移植、康复训练等干预措施，虽能够增强神经可塑性，在一定程度上改善神经缺陷行为，但因无法真正修复梗死区丢失的组织结构，这些措施的治疗效果是有限的。本项目应用人多能干细胞（hPSCs）定向分化技术在体外培育3D细胞组织——人脑类器官，并将基质胶Matrigel作为支持脑类器官3D结构的生物材料，移植到光照致皮层栓塞的免疫缺陷小鼠的梗死皮层，辅以环境丰富化训练，促进人脑类皮层在病灶区的存活及进一步分化为成熟神经元，并整合入正确的神经环路，修复梗死区的组织结构，最终消除卒中模式动物的神经缺陷行为，为尝试“治愈”卒中提供一种新的技术手段。

脑卒中是成人后天残疾的主要原因。卒中后的残疾通常是由梗死组织的永久性丢失所引起。然而，由于迄今尚未发现卒中后恢复期组织修复和功能重建的特异靶点，因此没有可用于促进恢复的药物疗法。目前正在探索各种干预措施，如干细胞移植和康复训练，以增强神经可塑性，从而在一定程度上改善神经缺陷行为。由于难以重建梗死区域的组织结构，这些干预措施的治疗效果有限。我们培养了源自人类多能干细胞（hPSCs）的三维（3D）细胞组织—人脑类器官，并将其移植到卒中NOD-SCID小鼠的梗死核心和梗死周围区域的交界处。几个月后，我们发现移植的类器官在梗死核心中存活良好，分化成皮层结构的目标神经元，修复梗死组织，将轴突发送到遥远的大脑目标，包括经胼胝体到对侧感觉运动皮层，同侧和对侧纹状体，丘脑并整合到宿主神经回路中。尤其重要的是，移植体能投射到脊髓形成皮质脊髓束。由于移植体在梗死区的存活及神经环路的整合，从而消除卒中小鼠的感觉运动缺陷行为，而从类器官分离的单个细胞的移植未能修复梗死组织。因此，我们的研究成果为通过类器官移植重建梗死组织提供了一种新的策略，从而逆转卒中导致的残疾。..我们的研究结果已在Stroke, Theranostics, Neurotherapeutics, Cereb Cortex，J Neurochem等杂志上发表了8篇文章。此外，一篇提交给NJP Regeneration Medicine和另一篇提交给Cell Reprots的文章在修稿中 。一项专利在项目实施期间获得授权。