Transcriptional profiling of macrophages derived from young and aged injured nerves at 3 days post-injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132882 | GEO | 2020/05/31
REPOSITORIES: GEO
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Project description:Pro-regenerative macrophages are well known for their role in promoting tissue repair, however in nerve injury their role in promoting regenerative events is not well defined. Macrophage-targeted RNAseq revealed that macrophages expressed an array of ligands post nerve injury that interact with the injury environement to regulate regeneration.
2018-07-31 | GSE106927 | GEO
Project description:The striking PNS regenerative response to injury rests on the plasticity of adult Schwann cells and their ability to transit between differentiation states, a highly unusual feature in mammals. Using mice with inactivation of Schwann cell c-Jun, we show that the injury response involves c-Jun dependent natural reprograming of differentiated cells to generate a distinct Schwann cell state specialized to promote regeneration. Transected distal stumps of c-Jun mutants show 172 disregulated genes, resulting in abnormal expression of growth factors, adhesion molecules and cytoskeletal changes that lead to neuronal death, inhibition of axon growth and striking failures of functional repair after injury. These observations provide a molecular basis for understanding Schwann cell plasticity and nerve regeneration. They offer conclusive support for the notion that Schwann cells control repair in the PNS, using dedicated transcriptional controls to generate a distinct repair cell, a transition that shows similarities to transdifferentiation seen in other systems. Total RNA was purified from a 10mm segment of the distal stump and uninjured contralateral nerve from c-Jun mutants and control mice 7 days after nerve cut. For each condition (injured/uninjured) and genotype (control/ knock-out) 2 independent samples (replicates) were generated from pooled nerves of 4/6 mice resulting in a total of 8 samples: CTRL.cut.R1, CTRL.cut.R2, CTRL.uncut.R1, CTRL.uncut.R2, KO.cut.R1, KO.cut.R2, KO.uncut.R1,KO.uncut.R2.
2012-06-13 | E-GEOD-38693 | biostudies-arrayexpress
Project description:Sciatic nerve crush (SNC) triggers sterile inflammation within the distal nerve and de-afferented dorsal root ganglia (DRGs). In the nerve, neutrophils and pro-inflammatory Ly6Chigh monocytes appear first and rapidly give way to Ly6Clow resolving macrophages. Transcriptional profiling of injured nerve tissue identifies six macrophage subpopulations, repair Schwann cells and mesenchymal cells as the main cell types. Macrophages at the nerve crush site are distinct from macrophages associated with degenerating nerve fibers. Monocytes and macrophages in the injured nerve “eat” apoptotic cell corpses of leukocytes and thereby contribute to an anti-inflammatory milieu. Studies with chimeric mice show that following SNC few blood-derived immune cells enter DRGs. Myeloid cells in the injured nerve, but not DRGs, express the receptor for the chemokine GM-CSF. In the absence of GM-CSF, conditioning-lesion induced regeneration of DRG neuron central projections is abrogated. Thus, a carefully orchestrated immune response in the nerve is required for conditioning-lesion induced neurorepair.
2021-03-17 | GSE153762 | GEO
Project description:The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.
2019-09-18 | GSE137504 | GEO
Project description:The striking PNS regenerative response to injury rests on the plasticity of adult Schwann cells and their ability to transit between differentiation states, a highly unusual feature in mammals. Using mice with inactivation of Schwann cell c-Jun, we show that the injury response involves c-Jun dependent natural reprograming of differentiated cells to generate a distinct Schwann cell state specialized to promote regeneration. Transected distal stumps of c-Jun mutants show 172 disregulated genes, resulting in abnormal expression of growth factors, adhesion molecules and cytoskeletal changes that lead to neuronal death, inhibition of axon growth and striking failures of functional repair after injury. These observations provide a molecular basis for understanding Schwann cell plasticity and nerve regeneration. They offer conclusive support for the notion that Schwann cells control repair in the PNS, using dedicated transcriptional controls to generate a distinct repair cell, a transition that shows similarities to transdifferentiation seen in other systems.
2012-06-14 | GSE38693 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a complex disease involving various cell types. Macrophages are essential in maintenance of physiological homeostasis, wound repair and fibrosis in the lung. Macrophages play a crucial role in repair and remodeling by altering their phenotype and secretory pattern in response to injury. The secretome of induced pluripotent stem cells (iPSC-cm) attenuates injury and fibrosis in bleomycin injured rat lungs. In the current study, we evaluate the effect of iPSC-cm on interstitial macrophage gene expression and phenotype in bleomycin injured rat lungs in vivo. Â iPSC-cm was intratracheally instilled 7 days after bleomycin induced lung injury and assessed 7 days later and single cell isolation was performed. Macrophages were FACS sorted and microarray analysis was performed. We characterized changes in the rat lung interstitial macrophages using transcriptional profiling.
2017-03-20 | E-MTAB-5619 | biostudies-arrayexpress
Project description:The multifaceted nature of neuroinflammation is highlighted by its ability to both aggravate and promote neuronal health. While in mammals retinal ganglion cells (RGCs) are unable to regenerate following injury, acute inflammation can induce axonal regrowth. However, the nature of the cells, cellular states and signalling pathways that drive this inflammation-induced regeneration have remained elusive. Here, we investigated the functional significance of macrophages during RGC de- and regeneration, by characterizing the inflammatory cascade evoked by optic nerve crush (ONC) injury, with or without local inflammatory stimulation in the vitreous. By combining single-cell RNA sequencing and fate mapping approaches, we elucidated the response of retinal microglia and recruited monocyte-derived macrophages (MDMs) to RGC injury. Importantly, inflammatory stimulation recruited large numbers of MDMs to the retina, which exhibited long-term engraftment and promoted axonal regrowth. Ligand-receptor analysis highlighted a subset of recruited macrophages that exhibited expression of pro-regenerative secreted factors, which were able to promote axon regrowth via paracrine signalling. Our work reveals how inflammation may promote CNS regeneration by modulating innate immune responses, providing a rationale for macrophage-centred strategies for driving neuronal repair following injury and disease.
2023-05-31 | GSE232470 | GEO
Project description:Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are essential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single-cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell-surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and CNS neurons, including known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesenchymal ligands, ANGPT1, CCL11, and VEGFC, promote growth when locally applied on sympathetic axons. These data therefore identify an unexpected paracrine role for nerve mesenchymal cells and suggest that multiple cell types contribute to creating a highly pro-growth environment for peripheral axons.
2020-05-06 | GSE146883 | GEO
Project description:Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.
2023-06-14 | GSE217172 | GEO
Project description:After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes a significant clinical problem. We find that aging and chronically denervated repair cells express reduced c-Jun protein and the regenerative support provided by these cells is also reduced. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. These experiments reveal that a common mechanism, reduced c-Jun in repair cells, underlies two major reasons for regeneration failure in the PNS. They underscore the central importance of Schwann cell c-Jun as a regulator of nerve repair, and point to molecular pathways that can be manipulated for improving the clinical outcome of nerve injuries.
2020-10-14 | E-MTAB-9640 | biostudies-arrayexpress