Intracerebral transplantation of HLA-homozygous human iPSC-derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke.
Intracerebral transplantation of HLA-homozygous human iPSC-derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke.
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HLA 纯合人类 iPSC 衍生神经前体的脑内移植可改善缺血性中风啮齿动物模型的行为和病理缺陷。
DOI：
10.1111/cpr.12884
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发表时间：
2020-09
影响因子：
8.5
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Noh JE;Oh SH;Lee S;Lee S;Kim YH;Park HJ;Ju JH;Kim HS;Huh JY;Song J
人诱导多能干细胞（hiPSC）是治疗缺血性卒中的有前途的细胞来源。尽管自体hiPSC提供了避免免疫排斥的优点，但其实际限制，例如产生单个iPSC系的大量时间和成本，阻碍了其在临床环境中的广泛应用。在这项研究中，我们研究了来自人类HLA纯合诱导多能干细胞（hiPSC-NPC）的神经前体细胞在脑内移植到大脑中动脉闭塞（MCAo）啮齿动物模型中后的治疗潜力。我们将GMP级HLA纯合hiPSC系（CMC ‐ hiPSC ‐ 004）分化为神经前体细胞，用于在缺血性卒中亚急性期（即诱导MCAo后7天）移植到大鼠体内。为了研究功能恢复，对移植动物进行了长达12周的五项行为测试，即旋转棒、踏步、mNSS、楼梯和阿扑吗啡诱导的旋转测试，然后进行组织学分析。我们观察到hiPSC-NPC移植产生了显著的行为改善。在移植后12周，高比例的移植细胞存活并分化成MAP 2+成熟神经元、GABA能神经元和DARPP 32+中等多刺神经元。移植的细胞与宿主脑中的纹状体神经元形成神经元连接。此外，hiPSC-NPC移植增强了内源性修复过程，包括卒中后神经炎症和神经胶质瘢痕形成减少以及室下区和病灶周围毛细血管网络中增殖的内源性神经干细胞增加。这些结果强烈表明HLA纯合hiPSC-NPC可用于治疗缺血性卒中患者。我们将源自HLA纯合hiPSC的神经前体细胞移植到亚急性期缺血性卒中大鼠中，并在旋转棒、踏步、mNSS、楼梯和阿扑吗啡诱导的旋转测试中观察到显著的行为改善。在移植后12周，高比例的移植细胞存活并分化成MAP 2+成熟神经元、GABA能神经元和DARPP 32+中等多刺神经元。移植的细胞与宿主脑中的纹状体神经元形成神经元连接。它们还引起增强的内源性修复过程，包括卒中后神经炎症和神经胶质瘢痕形成的减少以及室管膜下区和病灶周围毛细血管网络中增殖的内源性神经干细胞的增加。这些结果强烈表明，HLA纯合hiPSC-NPC可作为未来治疗缺血性卒中患者的有用候选物。
Human‐induced pluripotent stem cells (hiPSCs) are a promising cell source for treating ischaemic stroke. Although autologous hiPSCs provide the advantage of avoiding immune rejection, their practical limitations, such as substantial amount of time and costs to generate individual iPSC lines, have hampered their widespread application in clinical settings. In this study, we investigated the therapeutic potential of neural precursor cells derived from human HLA‐homozygous induced pluripotent stem cells (hiPSC‐NPCs) following intracerebral transplantation into a rodent model of middle cerebral artery occlusion (MCAo). We differentiated a GMP‐grade HLA‐homozygous hiPSC line (CMC‐hiPSC‐004) into neural precursor cells for transplantation into rats at the subacute stage of ischaemic stroke (ie at 7 days after the induction of MCAo). To investigate functional recovery, the transplanted animals were subjected to five behavioural tests, namely the rotarod, stepping, mNSS, staircase and apomorphine‐induced rotation tests, for up to 12 weeks, followed by histological analyses. We observed that the hiPSC‐NPC transplantation produced significant behavioural improvements. At 12 weeks post‐transplantation, a high proportion of transplanted cells survived and had differentiated into MAP2+ mature neurons, GABAergic neurons and DARPP32+ medium spiny neurons. The transplanted cells formed neuronal connections with striatal neurons in the host brain. In addition, hiPSC‐NPC transplantation gave rise to enhanced endogenous repair processes, including decreases of post‐stroke neuroinflammation and glial scar formation and an increase of proliferating endogenous neural stem cells in the subventricular zone as well as the perilesional capillary networks. These results strongly suggest that HLA‐homozygous hiPSC‐NPCs may be useful for treating ischaemic stroke patients. We transplanted neural precursor cells derived from HLA homozygous hiPSC into the subacute‐stage ischemic stroke rats and observed significant behavioral improvements in the rotarod, stepping, mNSS, staircase and apomorphine‐induced rotation tests. At 12 weeks post‐transplantation, a high proportion of transplanted cells survived and were differentiated into MAP2+ mature neurons, GABAergic neurons and DARPP32+ medium spiny neurons. Transplanted cells formed a neuronal connection with striatal neurons in the host brain. They also gave rise to enhanced endogenous repair processes, including the decrease of post‐stroke neuroinflammation and glial scar formation and the increase of proliferating endogenous neural stem cells in the subventricular zone as well as the perilesional capillary networks. These results strongly suggest that HLA‐homozygous hiPSC‐NPCs may serve as a useful candidate to treat ischemic stroke patients in the future.
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