Infiltrating cells from host brain restore the microglial population in grafted cortical tissue.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang C
PROVIDER: S-EPMC5018877 | biostudies-other | 2016
REPOSITORIES: biostudies-other
Publications
Infiltrating cells from host brain restore the microglial population in grafted cortical tissue.
Wang Cong C Tao Sijue S Fang Yukun Y Guo Jing J Zhu Lirui L Zhang Shengxiang S
Scientific reports 20160912
Transplantation of embryonic cortical tissue is considered as a promising therapy for brain injury. Grafted neurons can reestablish neuronal network and improve cortical function of the host brain. Microglia is a key player in regulating neuronal survival and plasticity, but its activation and dynamics in grafted cortical tissue remain unknown. Using two-photon intravital imaging and parabiotic model, here we investigated the proliferation and source of microglia in the donor region by transplan ...[more]
Similar Datasets
Project description:BACKGROUND:Although the therapeutic potential of bone marrow-derived stromal stem cells (BMSC) has been demonstrated in different experimental models of ischemic stroke, it remains unclear how stem cells (SC) induce neuroprotection following stroke. In this study, we describe a novel method for isolating BMSC that infiltrate postischemic brain tissue and use this method to identify the genes that are persistently activated or depressed in BMSC that infiltrate brain tissue following ischemic stroke. METHODS:Ischemic strokes were induced in C57BL/6 mice by middle cerebral artery occlusion for 1 h, followed by reperfusion. BMSC were isolated from H-2 Kb-tsA58 (immortomouse) mice, and were administered (i.v.) 24 h after reperfusion. At the peak of therapeutic improvement (14 days after the ischemic insult), infarcted brain tissue was isolated, and the BMSC were isolated by culturing at 33 degrees C. Microarray analysis and RT-PCR were performed to compare differential gene expression between naïve and infiltrating BMSC populations. RESULTS:Z-scoring revealed dramatic differences in the expression of extracellular genes between naïve and infiltrating BMSC. Pair-wise analysis detected 80 extracellular factor genes that were up-regulated (>/= 2 fold, P < 0.05, Benjamini-Hochberg correction) between naïve and infiltrated BMSC. Although several anticipated neuroregenerative, nerve guidance and angiogenic factor (e.g., bFGF, bone morphogenetic protein, angiopoietins, neural growth factor) genes exhibited an increased expression, a remarkable induction of genes for nerve guidance survival (e.g., cytokine receptor-like factor 1, glypican 1, Dickkopf homolog 2, osteopontin) was also noted. CONCLUSIONS:BMSC infiltrating the post-ischemic brain exhibit persistent epigenetic changes in gene expression for numerous extracellular genes, compared to their naïve counterparts. These genes are relevant to the neuroprotection, regeneration and angiogenesis previously described following stem cell therapy in animal models of ischemic stroke.
| S-EPMC2893124 | biostudies-literature
Project description:The brain remains one of the most important but least understood tissues in our body, in part because of its complexity as well as the limitations associated with in vivo studies. Although simpler tissues have yielded to the emerging tools for in vitro 3D tissue cultures, functional brain-like tissues have not. We report the construction of complex functional 3D brain-like cortical tissue, maintained for months in vitro, formed from primary cortical neurons in modular 3D compartmentalized architectures with electrophysiological function. We show that, on injury, this brain-like tissue responds in vitro with biochemical and electrophysiological outcomes that mimic observations in vivo. This modular 3D brain-like tissue is capable of real-time nondestructive assessments, offering previously unidentified directions for studies of brain homeostasis and injury.
| S-EPMC4183301 | biostudies-literature
Project description:Albumin, an abundant plasma protein with multifunctional properties, is mainly synthesized in the liver. Albumin has been implicated in Alzheimer's disease (AD) since it can bind to and transport amyloid beta (Abeta), the causative agent of AD; albumin is also a potent inhibitor of Abeta polymerization. Despite evidence of non-hepatic transcription of albumin in many tissues including kidney and pancreas, non-hepatic synthesis of albumin at the protein level has been rarely confirmed. In a pilot phase study of Human Brain Proteome Project, we found evidence that microglial cells in brain may synthesize albumin. Here we report, for the first time, the de novo synthesis of albumin in human microglial cells in brain. Furthermore, we demonstrate that the synthesis and secretion of albumin from microglial cells is enhanced upon microglial activation by Abeta(1-42)- or lipopolysaccharide (LPS)-treatment. These data indicate that microglial cells may play a beneficial role in AD by secreting albumin that not only inhibits Abeta polymerization but also increases its clearance.
| S-EPMC2483733 | biostudies-literature
Project description:The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis.
| S-EPMC3842117 | biostudies-literature
Project description:Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing ?-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b(+)c(+) myeloid cells. Both naïve- and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3(+) regulatory T cells circulated less than their conventional CD4(+) counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.
| S-EPMC4321317 | biostudies-literature
Project description:Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. Using rabies virus-based transsynaptic tracing, we find that at 6 mo after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons. We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side. Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.
| S-EPMC7183146 | biostudies-literature
Project description:The rational of neural stem cells (NSCs) in the therapy of neurological disease is either to replace dead neurons or to improve host neuronal survival, the latter of which has got less attention and the underlying mechanism is as yet little known. Using a transwell co-culture system, we reported that, in organotypic brain slice cultures, NSCs significantly improved host neuronal viability. Interestingly, this beneficial effect of NSCs was abrogated by a microglial inhibitor minocycline, while it was mimicked by a microglial agonist, Toll-like receptor 9 (TLR9) ligand CpG-ODN, which supports the pro-vital mediation by microglia on this NSCs-improved neuronal survival. Moreover, we showed that NSCs significantly induced host microglial movement and higher expression of a microglial marker IBA-1, the latter of which was positively correlated with TLR9 or extracellular-regulated protein kinases 1/2 (ERK1/2) activation. Real-time PCR revealed that NSCs inhibited the expression of pro-inflammatory molecules, but significantly increased the expression of molecules associated with a neuroprotective phenotype such as CX3CR1, triggering receptor expressed on myeloid cells-2 (TREM2) and insulin growth factor 1 (IGF-1). Similarly, in the microglia cells, NSCs induced the same microglial response as that in the slices. Further treatment with TLR9 ligand CpG-ODN, TLR9 inhibitor chloroquine (CQ) or ERK1/2 inhibitor U0126 demonstrated that TLR9-ERK1/2 pathway was involved in the NSCs-induced microglial activation. Collectively, this study indicated that NSCs improve host neuronal survival by switching microglia from a detrimental to a neuroprotective phenotype in adult mouse brain, and the microglial TLR9-ERK1/2 pathway seems to participate in this NSCs-mediated rescue action.
| S-EPMC4124015 | biostudies-literature
Project description:Infiltrating immune cells play a central role in degenerative joint disease associated with osteoarthritis (OA) and particle-mediated periprosthetic osteolysis. The goal of this study was to characterize a newly identified population of synovial tissue-infiltrating natural killer (NK) cells obtained from patients with OA or patients with periprosthetic joint inflammation.Synovial and interfacial tissue samples were collected from patients with OA who were undergoing primary or revision total joint replacement (TJR) surgery. The histologic features of OA synovium obtained from patients undergoing primary surgery and interfacial tissue obtained from patients undergoing revision surgery were determined by immunohistochemistry and immunofluorescence. Synovial tissue-infiltrating NK cells were evaluated for the expression of surface receptors, using flow cytometry. Chemoattractant and cytokine protein and RNA levels in synovial and interfacial tissue and fluid were assessed by Luminex assay and real-time quantitative polymerase chain reaction. Cytokine production and degranulation by stimulated synovial tissue versus normal blood NK cells were evaluated by intracellular cytokine staining.NK cells comprised nearly 30% of the CD45+ mononuclear cell infiltrate in synovial tissue obtained from patients undergoing primary TJR and from patients undergoing revision TJR. NK cells from both groups expressed CXCR3, CCR5, L-selectin, ?4 integrins, and cutaneous lymphocyte antigen. Synovial fluid from patients undergoing revision surgery contained elevated concentrations of the NK cell attractants CCL4, CCL5, CXCL9, and CXCL10; all levels in synovial fluid obtained from patients undergoing revision surgery were higher than those in synovial fluid from patients undergoing primary surgery. Cytokine-stimulated interferon-? production was significantly impaired in NK cells derived from primary and revision TJRs compared with blood NK cells.NK cells are a principal tissue-infiltrating lymphocyte subset in patients with OA and patients with periprosthetic inflammation and display a quiescent phenotype that is consistent with postactivation exhaustion.
| S-EPMC2995813 | biostudies-literature
Project description:Genes upregulated in stroke infiltrating stem cells were compared against the parent non-infiltrated mouse stem cell line derived from immortomouseTM. Abstract Background and Purpose- Although the therapeutic potential of bone marrow-derived stem cells (SC) has been addressed in different experimental models of ischemic stroke, it is still unclear how SC induce neuroprotection following stroke. In this study, we describe a novel method for recovering SC infiltrating post-stroke brain tissue allowing the determination of genes which become persistently activated / or depressed (compared to their naïve counterparts) during SC-mediated neuroprotection. Methods- Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion for 1 h, followed by reperfusion. SC were isolated from H-2Kb-tsA58 (immortomouseTM) mice, and were administered (i.v.) 24 h after reperfusion. At the onset of therapeutic improvement (14 days after ischemia), infarcted brain tissue was isolated and infarct-infiltratng SC cultured at 33°C. Microarray analysis and RT-PCR were performed to compare persistent differential gene expression between naïve and infiltrating SC populations. Results- Z-scoring revealed dramatic changes in extracellular genes of analyzed cells. Pair-wise analysis detected 80 extracellular factor genes that were up-regulated ( 2 fold, P<0.05, Benjamini-Hochberg correction) between naïve and infiltrated SC. Although several conventional neuroregenerative, nerve guidance and angiogenic factors (bFGF, bone morphogenetic protein, angiopoietins, neural growth factors were among the expressed genes detected we identified Cytokine receptor-like factor 1 (Crlf1), Fgf7, family with sequence similarity 19, member A5 (Fam19a5), Glypican 1 (Gpc1), Dickkopf homolog 2 (Dkk2), Endothelial cell-specific molecule 1, Osteopontin (OPN)35, Tissue factor pathway inhibitor 2, Masp3 mRNA for MBL-associated serine protease-3, Glial cell line derived neurotrophic factor (Gdnf), Bone morphogenetic protein 2 (Bmp2), Olfactomedin 1, Sushi-repeat-containing protein, X-linked 2 (Srpx2). Conclusions- SC infiltrating the post-i schemic brain assume a persistently altered pattern of expressed extracellular genes compared to naïve SC that contributes to neuroprotection, regeneration and angiogenesis in infarcts. Keywords: Gene activation / suppression study Comparison of persistent stem cell gene expression induced by stroke-infarct infiltration
2010-12-31 | E-GEOD-21393 | biostudies-arrayexpress
Project description:Traumatic brain injury (TBI) survivors suffer long term from mental illness, neurodegeneration, and neuroinflammation. Studies of 3D tissue models have provided new insights into the pathobiology of many brain diseases. Here, a 3D in vitro contusion model is developed consisting of mouse cortical neurons grown on a silk scaffold embedded in collagen and used outcomes from an in vivo model for benchmarking. Molecular, cellular, and network events are characterized in response to controlled cortical impact (CCI). In this model, CCI induces degradation of neural network structure and function and release of glutamate, which are associated with the expression of programmed necrosis marker phosphorylated Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL). Neurodegeneration is observed first in the directly impacted area and it subsequently spreads over time in 3D space. CCI reduces phosphorylated protein kinase B (pAKT) and Glycogen synthase kinase 3 beta (GSK3β) in neurons in vitro and in vivo, but discordant responses are observed in phosphprylated ribosomal S6 kinase (pS6) and phosphorylated Tau (pTau) expression. In summary, the 3D brain-like culture system mimicked many aspects of in vivo responses to CCI, providing evidence that the model can be used to study the molecular, cellular, and functional sequelae of TBI, opening up new possibilities for discovery of therapeutics.
| S-EPMC7395313 | biostudies-literature