Department of Neurosurgery, The Third Affiliated Hospital of The Third Military Medical University, Chongqing 400042, China; Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing 100038, China.
Brain Behav Immun. 2017 Jan;59:288-299. doi: 10.1016/j.bbi.2016.09.020. Epub 2016 Sep 17.
We previously reported that induced neural stem cells (iNSCs) directly reprogrammed from mouse embryonic fibroblasts can expand and differentiate into neurons, astrocytes and oligodendrocytes. Whether iNSCs have immunoregulatory properties in addition to facilitating cell replacement remains uncertain. In this study, we aimed to characterize the immunomodulatory effects of iNSCs on the activation states of microglia and to elucidate the mechanisms underlying these effects. Using a mouse model of closed head injury (CHI), we observed that iNSC grafts decreased the levels of ED1/Iba1 and TNF-α/Iba1 microglia but increased the levels of IGF1/Iba1 microglia in the injured cortex. Subsequently, using a Transwell co-culture system, we discovered that iNSCs could modulate LPS-pretreated microglia phenotypes in vitro via CXCL12/CXCR4 signaling, which we demonstrated through the administration of the CXCR4 antagonist AMD3100 and CXCR4-specific siRNA treatment. An in vivo loss-of-function study also revealed that iNSC grafts regulated the behavior of resident microglia via CXCL12/CXCR4 signaling, influencing their activation state such that they promoted neurological functional recovery and neuron survival. Furthermore, the beneficial effects of iNSC transplantation were significantly diminished by CXCR4 knockdown. In short, iNSCs have the potential to influence microglia activation and the acquisition of neuroprotective phenotypes via CXCL12/CXCR4 signaling.
我们之前报道过,从小鼠胚胎成纤维细胞直接重编程得到的诱导性神经干细胞(iNSCs)可以扩增并分化为神经元、星形胶质细胞和少突胶质细胞。除了促进细胞替代外,iNSCs 是否具有免疫调节特性仍不确定。在这项研究中,我们旨在表征 iNSCs 对小胶质细胞激活状态的免疫调节作用,并阐明这些作用的机制。我们使用闭合性颅脑损伤(CHI)小鼠模型观察到,iNSC 移植可降低损伤皮质中 ED1/Iba1 和 TNF-α/Iba1 小胶质细胞的水平,但增加 IGF1/Iba1 小胶质细胞的水平。随后,我们通过 Transwell 共培养系统发现,iNSCs 可以通过 CXCL12/CXCR4 信号调节 LPS 预处理的小胶质细胞表型,我们通过给予 CXCR4 拮抗剂 AMD3100 和 CXCR4 特异性 siRNA 处理证实了这一点。体内功能丧失研究也表明,iNSC 移植通过 CXCL12/CXCR4 信号调节常驻小胶质细胞的行为,影响其激活状态,从而促进神经功能恢复和神经元存活。此外,CXCR4 敲低显著减弱了 iNSC 移植的有益效果。总之,iNSCs 具有通过 CXCL12/CXCR4 信号影响小胶质细胞激活和获得神经保护表型的潜力。