Osman Ahmed M, Zhou Kai, Zhu Changlian, Blomgren Klas
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
Cell Transplant. 2014;23(12):1657-71. doi: 10.3727/096368913X674648. Epub 2013 Oct 22.
Radiotherapy is an effective treatment for brain tumors but often results in cognitive deficits in survivors. Transplantation of embryonic or brain-derived neural stem/progenitor cells (BNSPCs) ameliorated cognitive impairment after irradiation (IR) in animal models. However, such an approach in patients requires a clinically relevant source of cells. We show for the first time the utilization of enteric neural stem/progenitor cells (ENSPCs) from the postnatal intestinal wall as a source of autologous cells for brain repair after injury caused by IR. Cells were isolated from the intestinal wall and propagated in vitro for 1 week. Differentiation assays showed that ENSPCs are multipotent and generated neurons, astrocytes, and myofibroblasts. To investigate whether ENSPCs can be used in vivo, postnatal day 9 mice were subjected to a single moderate irradiation dose (6 or 8 Gy). Twelve days later, mice received an intrahippocampal injection of syngeneic ENSPCs. Four weeks after transplantation, 0.5% and 1% of grafted ENSPCs were detected in the dentate gyrus of sham and irradiated animals, respectively, and only 0.1% was detected after 16 weeks. Grafted ENSPCs remained undifferentiated but failed to restore IR-induced loss of BNSPCs and the subsequent impaired growth of the dentate gyrus. We observed microglia activation, astrogliosis, and loss of granule neurons associated with grafted ENSPC clusters. Transplantation of ENSPCs did not ameliorate IR-induced impaired learning and memory. In summary, while autologous ENSPC grafting to the brain worked technically, even in the absence of immunosuppression, the protocols need to be modified to improve survival and integration.
放射疗法是治疗脑肿瘤的有效方法，但常常会导致幸存者出现认知缺陷。在动物模型中，移植胚胎或脑源性神经干细胞/祖细胞（BNSPCs）可改善放疗（IR）后的认知障碍。然而，在患者中采用这种方法需要临床相关的细胞来源。我们首次展示了利用出生后肠壁的肠神经干细胞/祖细胞（ENSPCs）作为IR损伤后用于脑修复的自体细胞来源。从肠壁分离细胞并在体外培养1周。分化试验表明，ENSPCs具有多能性，可生成神经元、星形胶质细胞和肌成纤维细胞。为了研究ENSPCs是否可用于体内实验，对出生后第9天的小鼠给予单次中等剂量照射（6或8 Gy）。12天后，小鼠接受同基因ENSPCs的海马内注射。移植后4周，在假手术组和照射组动物的齿状回中分别检测到0.5%和1%的移植ENSPCs，16周后仅检测到0.1%。移植的ENSPCs保持未分化状态，但未能恢复IR诱导的BNSPCs丢失以及随后齿状回生长受损的情况。我们观察到与移植的ENSPCs簇相关的小胶质细胞激活、星形胶质细胞增生以及颗粒神经元丢失。ENSPCs移植并未改善IR诱导的学习和记忆障碍。总之，虽然将自体ENSPCs移植到脑中在技术上可行，即使在没有免疫抑制的情况下，仍需要修改方案以提高存活率和整合能力。
