Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Stem Cell Rev Rep. 2022 Feb;18(2):595-608. doi: 10.1007/s12015-021-10223-w. Epub 2021 Aug 28.
Human mesenchymal stem cells are a promising cell source for the treatment of stroke. Their primary mechanism of action occurs via neuroprotective effects by trophic factors, anti-inflammatory effects, and immunomodulation. However, the regeneration of damaged neuronal networks by cell transplantation remains challenging. We hypothesized that cells induced to neural lineages would fit the niche, replace the lesion, and be more effective in improving symptoms compared with stem cells themselves. We investigated the characteristics of induced neural cells from human dental pulp tissue and compared the transplantation effects between these induced neural cells and uninduced dental pulp stem cells. Induced neural cells or dental pulp stem cells were intracerebrally transplanted 5 days after cerebral infarction induced by permanent middle cerebral artery occlusion in immunodeficient mice. Effects on functional recovery were also assessed through behavior testing. We used immunohistochemistry and neuron tracing to analyze the differentiation, axonal extension, and connectivity of transplanted cells to the host's neural circuit. Transplantation of induced neural cells from human dental pulp ameliorated functional recovery after cerebral infarction compared with dental pulp stem cells. The induced neural cells comprised both neurons and glia and expressed functional voltage, and they were more related to neurogenesis in terms of transcriptomics. Induced neural cells had a higher viability than did dental pulp stem cells in hypoxic culture. We showed that induced neural cells from dental pulp tissue offer a novel therapeutic approach for recovery after cerebral infarction.
人牙髓间充质干细胞是治疗中风有前途的细胞来源。它们的主要作用机制是通过神经营养因子、抗炎作用和免疫调节产生神经保护作用。然而，通过细胞移植来再生受损的神经网络仍然具有挑战性。我们假设诱导为神经谱系的细胞将适应微环境，替代病变部位，并在改善症状方面比干细胞本身更有效。我们研究了人牙髓组织来源的诱导神经细胞的特征，并比较了这些诱导神经细胞和未诱导牙髓干细胞的移植效果。在免疫缺陷小鼠永久性大脑中动脉闭塞诱导脑梗死 5 天后，将诱导的神经细胞或牙髓干细胞脑内移植。通过行为测试评估对功能恢复的影响。我们使用免疫组织化学和神经元示踪来分析移植细胞向宿主神经回路的分化、轴突延伸和连接。与牙髓干细胞相比，人牙髓来源的诱导神经细胞移植可改善脑梗死后的功能恢复。诱导的神经细胞包括神经元和神经胶质细胞，并表达功能性电压，在转录组学方面与神经发生更相关。在低氧培养中，诱导的神经细胞比牙髓干细胞具有更高的活力。我们表明，牙髓组织来源的诱导神经细胞为脑梗死后的恢复提供了一种新的治疗方法。
