Islam Rehnuma, Drecun Stasja, Varga Balazs V, Vonderwalde Ilan, Siu Ricky, Nagy Andras, Morshead Cindi M
Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
Front Cell Neurosci. 2021 Apr 29;15:654290. doi: 10.3389/fncel.2021.654290. eCollection 2021.
Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (<6%) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.
中风是全球范围内导致死亡和长期残疾的主要原因。目前的治疗选择在实施时间和促进恢复的疗效方面都很有限。细胞移植在几种动物模型中已显示出前景，但仍存在重大挑战，包括促进神经修复的最佳细胞来源。在此，我们报告了使用一群源自人胚胎干细胞、经皮质定向的神经上皮前体细胞（cNEPs），其谱系潜能受神经限制。cNEPs在移植后有产生成熟神经细胞类型的潜力，包括神经元、星形胶质细胞和少突胶质细胞。为了实现转化应用，我们试图确定这种人类细胞来源在促进中风后功能改善方面是否有效。将未分化的cNEPs移植到免疫缺陷的SCID-米色小鼠的缺血性运动皮质中风的临床前内皮素-1（ET-1）模型中，并评估细胞和功能结果。我们证明，与中风损伤但未移植的小鼠相比，在急性期（中风后4天）进行cNEP移植可早在中风后20天改善运动功能。在恢复时，在中风损伤部位观察到一小部分（<6%）移植的cNEPs。存活的细胞表达未成熟神经元标志物双皮质素，未分化为成熟神经表型。在更长的存活时间（40天），大多数恢复的移植小鼠完全没有存活的cNEPs。因此，在中风后早期移植的人cNEPs支持ET-1中风后观察到的功能恢复，但它们的持续存在并非必需，从而支持旁分泌效应而非细胞替代。
