title: Induced neural stem cells modulate microglia activation states via CXCL12/CXCR4 signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mou
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing 100038, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Hongtian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of The Third Military Medical University, Chongqing 400042, China. Electronic address: dpmhxu@126.com.
authors.forename: Minhui
authors.initials: M
authors.lastname: Xu
authors.affiliation: Affiliated Bayi Brain Hospital, P.L.A Army General Hospital, Beijing 100700, China. Electronic address: jzprofxu@126.com.
authors.forename: Ruxiang
authors.initials: R
authors.lastname: Xu
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics*; D053331:Ectodysplasins / Q000378:metabolism; D016489:Head Injuries, Closed / Q000473:pathology; D057026:Induced Pluripotent Stem Cells; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; C514936:CXCR4 protein, mouse; D002135:Calcium-Binding Proteins; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053331:Ectodysplasins; C506019:Eda protein, mouse; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha
keywords: CXCR4; Closed head injury; Immunomodulation; Induced neural stem cell; Microglia