Jing Li1, Hualong Wang1, Chongbo Du1, Xiaojing Jin1, Yuan Geng1, Bing Han1, Qinying Ma1, Quanhai Li2, Qian Wang3, Yidi Guo3, Mingwei Wang4, Baoyong Yan5. 1. Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, China; Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei Province, Shijiazhuang, Hebei 050017, China. 2. Cell Therapy Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050031, China; Department of Immunology, Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. 3. Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. 4. Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, China; Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei Province, Shijiazhuang, Hebei 050017, China. Electronic address: mingweiwang88@163.com. 5. Cell Therapy Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050031, China. Electronic address: yanby7001@163.com.
Abstract
BACKGROUND: Major depressive disorder (MDD) has been shown to be related to immune inflammation and the complement system. Previous studies have suggested that human umbilical cord mesenchymal stem cells (hUC-MSCs) play an important role in inflammatory diseases. METHODS: hUC-MSCs were administered into chronic unpredictable mild stress model (CUMS) mice through the tail vein once a week for 4 weeks. After the administration of hUC-MSCs, the depression-like and anxiety-like phenotypes, neuronal histopathology, synaptic-related protein expression and inflammatory index of the mice were assessed. Microglial M1/M2 polarization and the expression of C3a in astrocytes and C3aR in microglia was detected by immunofluorescence co-localization. Then, CUMS mice were injected with a C3aR antagonist, and the expression of C3a and C3aR and microglial polarization were observed. RESULTS: Based on the sucrose preference and tail suspension tests, hUC-MSCs ameliorated the depression-like behaviors of CUMS mice. Additionally, the anxiety-like behaviors of CUMS mice in the open-field and plus-maze tests were improved after the administration of hUC-MSCs. hUC-MSCs altered microglia polarization by alleviating complement C3a-C3aR signaling activation, which decreased pro-inflammatory factor levels and increased anti-inflammatory factor levels, alleviating neuronal damage and synaptic deficits. CONCLUSION: hUC-MSCs have therapeutic effects on anxiety-like and depressive-like phenotypes caused by CUMS. They can alter the polarization of microglia by inhibiting C3a-C3aR signaling to reduce neuroinflammation.
BACKGROUND: Major depressive disorder (MDD) has been shown to be related to immune inflammation and the complement system. Previous studies have suggested that human umbilical cord mesenchymal stem cells (hUC-MSCs) play an important role in inflammatory diseases. METHODS: hUC-MSCs were administered into chronic unpredictable mild stress model (CUMS) mice through the tail vein once a week for 4 weeks. After the administration of hUC-MSCs, the depression-like and anxiety-like phenotypes, neuronal histopathology, synaptic-related protein expression and inflammatory index of the mice were assessed. Microglial M1/M2 polarization and the expression of C3a in astrocytes and C3aR in microglia was detected by immunofluorescence co-localization. Then, CUMS mice were injected with a C3aR antagonist, and the expression of C3a and C3aR and microglial polarization were observed. RESULTS: Based on the sucrose preference and tail suspension tests, hUC-MSCs ameliorated the depression-like behaviors of CUMS mice. Additionally, the anxiety-like behaviors of CUMS mice in the open-field and plus-maze tests were improved after the administration of hUC-MSCs. hUC-MSCs altered microglia polarization by alleviating complement C3a-C3aR signaling activation, which decreased pro-inflammatory factor levels and increased anti-inflammatory factor levels, alleviating neuronal damage and synaptic deficits. CONCLUSION: hUC-MSCs have therapeutic effects on anxiety-like and depressive-like phenotypes caused by CUMS. They can alter the polarization of microglia by inhibiting C3a-C3aR signaling to reduce neuroinflammation.