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1.
Nat Commun ; 12(1): 5501, 2021 09 17.
Article in English | MEDLINE | ID: mdl-34535655

ABSTRACT

Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.


Subject(s)
Central Nervous System/pathology , Cicatrix/pathology , Pericytes/pathology , Aging/physiology , Animals , Astrocytes/pathology , Brain Injuries, Traumatic/pathology , Brain Ischemia/pathology , Brain Neoplasms/pathology , Cerebral Cortex/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Extracellular Matrix/metabolism , Fibroblasts/pathology , Fibrosis , Glioblastoma/pathology , Humans , Ischemic Stroke/pathology , Mice, Inbred C57BL , Mice, Transgenic , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments , Receptor, Platelet-Derived Growth Factor beta/metabolism , Spinal Cord/pathology , Spinal Cord/ultrastructure , Spinal Cord Injuries/pathology , Stromal Cells/pathology
2.
Proc Natl Acad Sci U S A ; 118(33)2021 08 17.
Article in English | MEDLINE | ID: mdl-34389674

ABSTRACT

Astrocytes have emerged as a potential source for new neurons in the adult mammalian brain. In mice, adult striatal neurogenesis can be stimulated by local damage, which recruits striatal astrocytes into a neurogenic program by suppression of active Notch signaling (J. P. Magnusson et al., Science 346, 237-241 [2014]). Here, we induced adult striatal neurogenesis in the intact mouse brain by the inhibition of Notch signaling in astrocytes. We show that most striatal astrocyte-derived neurons are confined to the anterior medial striatum, do not express established striatal neuronal markers, and exhibit dendritic spines, which are atypical for striatal interneurons. In contrast to striatal neurons generated during development, which are GABAergic or cholinergic, most adult astrocyte-derived striatal neurons possess distinct electrophysiological properties, constituting the only glutamatergic striatal population. Astrocyte-derived neurons integrate into the adult striatal microcircuitry, both receiving and providing synaptic input. The glutamatergic nature of these neurons has the potential to provide excitatory input to the striatal circuitry and may represent an efficient strategy to compensate for reduced neuronal activity caused by aging or lesion-induced neuronal loss.


Subject(s)
Astrocytes/physiology , Connexin 30/metabolism , Glutamic Acid/metabolism , Neurons/physiology , Animals , Cell Differentiation , Connexin 30/genetics , Deoxyuridine/analogs & derivatives , Deoxyuridine/pharmacology , Electrophysiological Phenomena , GABAergic Neurons/enzymology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Interneurons/enzymology , Luminescent Proteins , Mice , Mice, Transgenic , Nitric Oxide Synthase Type I/genetics , Nitric Oxide Synthase Type I/metabolism , Recombination, Genetic , Tamoxifen/pharmacology
3.
Science ; 346(6206): 237-41, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25301628

ABSTRACT

Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 ± 210 (mean ± SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies.


Subject(s)
Astrocytes/physiology , Neural Stem Cells/physiology , Neurogenesis/physiology , Neurons/physiology , Receptor, Notch1/physiology , Signal Transduction , Stroke/physiopathology , Animals , Astrocytes/cytology , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Gene Deletion , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Stem Cells/cytology , Neurogenesis/genetics , Neurons/cytology , Receptor, Notch1/genetics , Stroke/pathology
4.
Science ; 342(6158): 637-40, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24179227

ABSTRACT

Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell-derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.


Subject(s)
Apoptosis , Axons/physiology , Cicatrix/pathology , Neural Stem Cells/physiology , Spinal Cord Injuries/pathology , Animals , Astrocytes/physiology , Cell Survival , Forkhead Transcription Factors/genetics , Genes, ras , Mice , Mice, Mutant Strains
5.
Science ; 333(6039): 238-42, 2011 Jul 08.
Article in English | MEDLINE | ID: mdl-21737741

ABSTRACT

There is limited regeneration of lost tissue after central nervous system injury, and the lesion is sealed with a scar. The role of the scar, which often is referred to as the glial scar because of its abundance of astrocytes, is complex and has been discussed for more than a century. Here we show that a specific pericyte subtype gives rise to scar-forming stromal cells, which outnumber astrocytes, in the injured spinal cord. Blocking the generation of progeny by this pericyte subtype results in failure to seal the injured tissue. The formation of connective tissue is common to many injuries and pathologies, and here we demonstrate a cellular origin of fibrosis.


Subject(s)
Cicatrix/pathology , Pericytes/pathology , Spinal Cord Injuries/pathology , Spinal Cord/pathology , Animals , Astrocytes/pathology , Astrocytes/physiology , Blood Vessels/pathology , Cell Count , Cell Proliferation , Fibrosis , Mice , Mice, Transgenic , Pericytes/physiology , Spinal Cord/blood supply , Stromal Cells/pathology
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