Neural progenitor cells (NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox (VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR (0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition (5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6 (Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs (ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson's disease.

中文翻译：

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低氧条件下小分子化合物诱导的成纤维细胞神经祖细胞用于治疗大鼠帕金森病。

能够自我更新和分化为神经细胞谱系的神经祖细胞 (NPC) 为神经退行性疾病的细胞治疗提供了广阔的前景。然而，基于 NPC 移植的细胞疗法因无法获得足够数量的 NPC 而受到限制。先前的研究发现，丙戊酸、CHIR99021 和 Repsox (VCR) 的化学混合物可促进小鼠成纤维细胞在缺氧条件下分化为 NPC。因此，我们使用 VCR（0.5 mM 丙戊酸、3 μM C​​HIR99021 和 1 μM Repsox）在缺氧条件下 (5%) 诱导大鼠胚胎成纤维细胞重编程为 NPC。这些 NPC 表现出典型的神经球样结构，可以表达 NPC 标记，例如 Nestin、SRY-box 转录因子 2 和配对框 6 (Pax6)，并且还可以在体外分化为多种类型的功能神经元和星形胶质细胞。它们具有与大鼠脑源性神经干细胞相似的基因表达谱。随后，化学诱导的 NPC (ciNPC) 被立体定向​​移植到 6-羟基多巴胺损伤的帕金森大鼠的黑质中。我们发现 ciNPCs 在体内表现出长期存活、长距离迁移并分化为多种类型的功能神经元和神经胶质细胞。此外，移植ciNPCs的帕金森模型大鼠的帕金森行为缺陷表现出显着的功能恢复。这些发现表明，大鼠成纤维细胞可以使用 VCR 的化学混合物直接转化为 NPC，而无需引入外源因素，