Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation.
Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation.
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DOI：
10.3727/096368913x670200
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发表时间：
2014
影响因子：
3.3
通讯作者：
Limoli CL
中科院分区：
文献类型：
--
作者：
Acharya MM;Christie LA;Hazel TG;Johe KK;Limoli CL
中枢神经系统恶性肿瘤的治疗通常包括放射治疗，以防止肿瘤生长和手术切除后复发。尽管颅放射治疗有许多好处，但幸存者往往会遭受广泛的衰弱和进行性认知缺陷。因此，虽然患有原发性和继发性CNS恶性肿瘤的患者现在经历了更长的局部区域控制和无进展生存期，但仍然没有与癌症治疗相关的非预期神经认知后遗症的临床追索权。多种机制导致辐射后认知功能受损，包括海马体中干细胞和祖细胞的辐射敏感群体的耗竭。我们已经探索了利用海马内移植人类干细胞来改善辐射诱导的认知功能障碍的潜力。过去的研究表明，颅骨移植的人胚胎干细胞（hESC）和神经干细胞（hNSCs）的能力，以功能恢复大鼠的认知后1和4个月的头部照射。本研究采用了FDA批准的胎儿来源的人神经干细胞系，能够在良好生产规范（GMP）下大规模生产。接受这些细胞照射后1个月的颅骨移植的动物表现出改善海马空间记忆和上下文恐惧条件反射性能相比，照射，假手术对照。显著的新生（doublecortin阳性）神经元和一小部分的胶质细胞亚型内和附近的移植核心。移植的细胞迁移和分化成神经元和神经胶质细胞亚型在整个CA1和CA3子域的宿主海马。这些研究扩展了我们先前的发现，证明胚胎来源的人神经干细胞移植改善了受辐射动物的认知缺陷，通过两个独立的认知任务进行评估。
Treatment of CNS malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4-months post-head-only irradiation. The present study employed an FDA-approved fetal-derived human neural stem cell line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1-month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived human neural stem cells improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.