Acharya Munjal M, Christie Lori-Ann, Hazel Thomas G, Johe Karl K, Limoli Charles L
Department of Radiation Oncology, University of California, Irvine, CA, USA.
Cell Transplant. 2014;23(10):1255-66. doi: 10.3727/096368913X670200. Epub 2013 Jul 17.
Treatment of central nervous system (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 after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC 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 hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.
中枢神经系统（CNS）恶性肿瘤的治疗通常包括放疗，以防止手术切除后肿瘤生长和复发。尽管颅脑放疗有诸多益处，但幸存者常常遭受各种使人衰弱且不断进展的认知缺陷。因此，虽然患有中枢神经系统原发性和继发性恶性肿瘤的患者现在局部区域控制时间更长且无进展生存期延长，但对于与其癌症治疗相关的意外神经认知后遗症仍没有临床应对措施。多种机制导致放疗后认知功能受损，包括海马中放射敏感性干细胞和祖细胞群的耗竭。我们探讨了通过海马内移植人类干细胞来改善放疗诱导的认知功能障碍的可能性。过去的研究表明，颅脑移植的人类胚胎干细胞（hESCs）和神经干细胞（hNSCs）能够在颅脑放疗后1个月和4个月在功能上恢复大鼠的认知能力。本研究采用了一种经美国食品药品监督管理局（FDA）批准的、可在良好生产规范（GMP）下大规模扩增的胎儿来源的hNSC系。与接受放疗的假手术对照组相比，在放疗后1个月接受这些细胞颅脑移植的动物海马空间记忆和情境恐惧条件反射表现有所改善。在移植核心及其附近观察到大量新生的（双皮质素阳性）神经元和较小比例的胶质细胞亚型。移植的细胞迁移并分化为宿主海马CA1和CA3亚区的神经元和胶质细胞亚型。这些研究扩展了我们之前的发现，表明通过两项独立的认知任务评估，胎儿来源的hNSCs移植可改善受辐照动物的认知缺陷。
