Ectoderm-derived frontal bone mesenchymal stem cells promote traumatic brain injury recovery by alleviating neuroinflammation and glutamate excitotoxicity partially via FGF1

Abstract

Background Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model. Methods A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits. Ectoderm-derived FbMSCs were isolated from the frontal bone and their characteristics were assessed using multiple differentiation assays, flow cytometry and microarray analysis. Brain repairment and functional recovery were analyzed at different days post-injury with or without FbMSC application. Behavioral tests were performed to assess learning and memory improvements. RNA sequencing analysis, immunofluorescence staining, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to examine inflammation reaction and neural regeneration. In vitro co-culture analysis and quantification of glutamate transportation were carried out to explore the possible mechanism of neurogenesis and functional recovery promoted by FbMSCs. Results Ectoderm-derived FbMSCs showed fibroblast like morphology and osteogenic differentiation capacity. FbMSCs were CD105, CD29 positive and CD45, CD31 negative. Different from mesoderm-derived MSCs, FbMSCs expressed the ectoderm-specific transcription factor Tfap2β. TBI mice showed impaired learning and memory deficits. Microglia and astrocyte activation, as well as neural damage, were significantly increased post-injury. FbMSC application ameliorated the behavioral deficits of TBI mice and promoted neural regeneration. RNA sequencing analysis showed that signal pathways related to inflammation decreased, whereas those related to neural activation increased. Immunofluorescence staining and qRT-PCR data revealed that microglial activation and astrocyte polarization to the A1 phenotype were suppressed by FbMSC application. In addition, FGF1 secreted from FbMSCs enhanced glutamate transportation by astrocytes and alleviated the cytotoxic effect of excessive glutamate on neurons. Conclusions Ectoderm-derived FbMSC application significantly alleviated neuroinflammation, brain injury, and excitatory toxicity to neurons, improved cognition and behavioral deficits in TBI mice. Therefore, ectoderm-derived FbMSCs could be ideal therapeutic candidates for TBI which mostly affect cells from the same embryonic origins as FbMSCs.

Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease

“…TGFβ1 promotes neurogenesis by promoting quiescent microglia in mouse models of prion disease (Boche et al, 2006;De Lucia et al, 2016). VEGF promotes angiogenesis and tissue repair and decreases inflammatory cytokines in the brain (Xu et al, 2017), and FGF downregulates NF-κB signaling in microglia and decreases astrogliosis in models of traumatic brain injury (Dordoe et al, 2022;Qin et al, 2022). Together, this data suggests that stimulation of AdMSCs with inflammatory cytokines such as TNFα increases their production of protective molecules.…”

Neuroblasts migration under control of reactive astrocyte-derived BDNF: a promising therapy in late neurogenesis after traumatic brain injury

“…At present, there are no effective therapeutic strategies for severe neurological dysfunction in TBI patients. Numerous works have proven that stem cell therapy and neurogenesis can ameliorate brain injury in experimental models of TBI and other diseases [4 – 13] . However, the pattern and mechanism of endogenous neuroblasts migration after TBI is still unclear.…”

“…Traumatic brain injury (TBI) is a disease with high mortality and morbidity, which leads to severe neurological dysfunction, such as severe motor, neural psychological, and cognitive disabilities [1 – 4] . Despite extensive researches, there is still no ideal treatment for TBI due to multiple complications during pathogenesis [2 , 4] .…”

“…However, this belief was subverted when postnatal and adult stem cells from the mammalian subventricular zone (SVZ) and subgranular zone (SGZ) had been rediscovered [5] . Up to now, stem cell therapy and neurogenesis have provided therapeutic options for treating TBI [4 , 6] .…”

Fibroblast growth factor 1 ameliorates thin endometrium in rats through activation of the autophagic pathway

“…Fibroblast growth factor 1 (FGF1), also known as acid FGF, which is involved in tissue regeneration, trauma repair and metabolism ( Hwang et al, 2022 ; Li et al, 2022 ; Qin et al, 2022 ; Sancar et al, 2022 ). However, in recent years, numerous studies have indicated that FGF1 also appeared to have an effect on the endometrium ( Okumu et al, 2014 ; Kato et al, 2019 ).…”