RESUMO
Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Importantly, in vivo infection triggered the death of uninfected as well as infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in PML may be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination may provide an especially favorable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.
RESUMO
The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.
Assuntos
Estresse do Retículo Endoplasmático , Longevidade , Animais , Longevidade/fisiologia , Resposta a Proteínas não Dobradas , Transcriptoma , Ratos-ToupeiraRESUMO
Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT. Comparison of differential gene expression across these conditions, all with respect to normal HTT controls, reveals cell-type-specific changes in transcription common to both species, yet with differences that distinguish glia expressing truncated mHTT versus full-length mHTT. These data indicate that the differential gene expression of glia expressing truncated mHTT may differ from that of cells expressing full-length mHTT, while identifying a conserved set of dysregulated pathways in HD glia.
Assuntos
Doença de Huntington/patologia , Neuroglia/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Vias Biossintéticas , Colesterol/biossíntese , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Camundongos Endogâmicos C57BL , Proteínas Mutantes/metabolismo , Neuroglia/metabolismo , Transcrição GênicaRESUMO
Neonatally transplanted human glial progenitor cells (hGPCs) can myelinate the brains of myelin-deficient shiverer mice, rescuing their phenotype and survival. Yet, it has been unclear whether implanted hGPCs are similarly able to remyelinate the diffusely demyelinated adult CNS. We, therefore, ask if hGPCs could remyelinate both congenitally hypomyelinated adult shiverers and normal adult mice after cuprizone demyelination. In adult shiverers, hGPCs broadly disperse and differentiate as myelinating oligodendrocytes after subcortical injection, improving both host callosal conduction and ambulation. Implanted hGPCs similarly remyelinate denuded axons after cuprizone demyelination, whether delivered before or after demyelination. RNA sequencing (RNA-seq) of hGPCs back from cuprizone-demyelinated brains reveals their transcriptional activation of oligodendrocyte differentiation programs, while distinguishing them from hGPCs not previously exposed to demyelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to broadly myelinate regions of dysmyelination, and also to be recruited as myelinogenic oligodendrocytes later in life, upon demyelination-associated demand.
Assuntos
Encéfalo/fisiopatologia , Doenças Desmielinizantes/genética , Neuroglia/metabolismo , Células-Tronco/metabolismo , Animais , Diferenciação Celular , Humanos , CamundongosRESUMO
Astrocytic differentiation is developmentally impaired in patients with childhood-onset schizophrenia (SCZ). To determine why, we used genetic gain- and loss-of-function studies to establish the contributions of differentially expressed transcriptional regulators to the defective differentiation of glial progenitor cells (GPCs) produced from SCZ patient-derived induced pluripotent cells (iPSCs). Negative regulators of the bone morphogenetic protein (BMP) pathway were upregulated in SCZ GPCs, including BAMBI, FST, and GREM1, whose overexpression retained SCZ GPCs at the progenitor stage. SMAD4 knockdown (KD) suppressed the production of these BMP inhibitors by SCZ GPCs and rescued normal astrocytic differentiation. In addition, the BMP-regulated transcriptional repressor REST was upregulated in SCZ GPCs, and its KD similarly restored normal glial differentiation. REST KD also rescued potassium-transport-associated gene expression and K+ uptake, which were otherwise deficient in SCZ glia. These data suggest that the glial differentiation defect in childhood-onset SCZ, and its attendant disruption in K+ homeostasis, may be rescued by targeting BMP/SMAD4- and REST-dependent transcription.
Assuntos
Diferenciação Celular , Neuroglia/metabolismo , Proteínas Repressoras/metabolismo , Esquizofrenia/metabolismo , Transdução de Sinais , Proteína Smad4/metabolismo , Adolescente , Adulto , Linhagem Celular , Criança , Feminino , Humanos , Masculino , Neuroglia/patologia , Proteínas Repressoras/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Proteína Smad4/genéticaRESUMO
Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2.2, OLIG2, SOX10, MYRF, and their downstream targets were all suppressed. Accordingly, when mHTT hGPCs were transplanted into hypomyelinated shiverer mice, the resultant glial chimeras were hypomyelinated; this defect could be rescued by forced expression of SOX10 and MYRF by mHTT hGPCs. The mHTT hGPCs also manifested impaired astrocytic differentiation and developed abnormal fiber architecture. White matter involution in HD is thus a product of the cell-autonomous, mHTT-dependent suppression of glial differentiation.
Assuntos
Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Células-Tronco Embrionárias Humanas/patologia , Proteína Huntingtina/genética , Doença de Huntington/patologia , Neuroglia/patologia , Células-Tronco/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Diferenciação Celular , Quimera , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Camundongos , Mutação , Neurogênese , Neuroglia/metabolismo , Proteínas Nucleares , Células-Tronco/metabolismo , Fatores de TranscriçãoRESUMO
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.
Assuntos
Quimera/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Neuroglia/patologia , Esquizofrenia/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Comportamento , Diferenciação Celular/genética , Regulação da Expressão Gênica , Humanos , Camundongos , Bainha de Mielina/metabolismo , Neuroglia/metabolismo , Fenótipo , Esquizofrenia/genéticaRESUMO
Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.
Assuntos
Oligodendroglia/patologia , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/patologia , Técnicas de Cultura de Células , Criança , Pré-Escolar , Estresse do Retículo Endoplasmático , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Proteína Proteolipídica de Mielina , Oligodendroglia/metabolismoRESUMO
Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutation in the proteolipid protein-1 (PLP1) gene, which encodes the proteolipid protein of myelinating oligodendroglia. PMD exhibits phenotypic variability that reflects its considerable genotypic heterogeneity, but all forms of the disease result in central hypomyelination, associated in most cases with early neurological dysfunction, progressive deterioration, and ultimately death. PMD may present as a connatal, classic and transitional forms, or as the less severe spastic paraplegia type 2 and PLP-null phenotypes. These disorders are most often associated with duplications of the PLP1 gene, but can also be caused by coding and noncoding point mutations as well as full or partial deletion of the gene. A number of genetically-distinct but phenotypically-similar disorders of hypomyelination exist which, like PMD, lack any effective therapy. Yet as relatively pure CNS hypomyelinating disorders, with limited involvement of the PNS and relatively little attendant neuronal pathology, PMD and similar hypomyelinating disorders are attractive therapeutic targets for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of research centers. Stem Cells 2017;35:311-315.
Assuntos
Doença de Pelizaeus-Merzbacher/terapia , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Modelos Animais de Doenças , Humanos , Mutação/genética , Bainha de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/patologiaRESUMO
The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.
Assuntos
Doença de Huntington/patologia , Neuroglia/patologia , Animais , Comportamento Animal , Quimera/metabolismo , Cognição , Cruzamentos Genéticos , Progressão da Doença , Feminino , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Proteína Huntingtina/metabolismo , Receptores de Hialuronatos/metabolismo , Masculino , Camundongos , Atividade Motora , Neostriado/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Fenótipo , Transplante de Células-Tronco , Análise de SobrevidaRESUMO
As new methods for producing and isolating human glial progenitor cells (hGPCs) have been developed, the disorders of myelin have become especially compelling targets for cell-based therapy. Yet as animal modeling of glial progenitor cell-based therapies has progressed, it has become clear that transplanted hGPCs not only engraft and expand within murine hosts, but dynamically outcompete the resident progenitors so as to ultimately dominate the host brain. The engrafted human progenitor cells proceed to generate parenchymal astrocytes, and when faced with a hypomyelinated environment, oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human cognition and information processing. In addition, the cellular humanization of these brains permits their use in studying glial infectious and inflammatory disorders unique to humans, and the effects of those disorders on the glial contributions to cognition. Perhaps most intriguingly, by pairing our ability to construct human glial chimeras with the production of patient-specific hGPCs derived from pluripotential stem cells, we may now establish mice in which a substantial proportion of resident glia are both human and disease-derived. These mice in particular may provide us new opportunities for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human neurological and neuropsychiatric disease.
Assuntos
Doenças do Sistema Nervoso Central/fisiopatologia , Cognição/fisiologia , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplante , Neuroglia/citologia , Neuroglia/fisiologia , Animais , Doenças do Sistema Nervoso Central/cirurgia , Quimera , Humanos , Camundongos , Modelos AnimaisRESUMO
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.
Assuntos
Astrócitos/imunologia , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Transplante de Células-Tronco , Células-Tronco/imunologia , Quimeras de Transplante/imunologia , Replicação Viral/imunologia , Animais , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/imunologia , Apoptose/genética , Apoptose/imunologia , Astrócitos/patologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Leucoencefalopatia Multifocal Progressiva/genética , Leucoencefalopatia Multifocal Progressiva/patologia , Masculino , Camundongos , Células-Tronco/patologiaRESUMO
Neonatally transplanted human glial progenitor cells (hGPCs) densely engraft and myelinate the hypomyelinated shiverer mouse. We found that, in hGPC-xenografted mice, the human donor cells continue to expand throughout the forebrain, systematically replacing the host murine glia. The differentiation of the donor cells is influenced by the host environment, such that more donor cells differentiated as oligodendrocytes in the hypomyelinated shiverer brain than in myelin wild-types, in which hGPCs were more likely to remain as progenitors. Yet in each recipient, both the number and relative proportion of mouse GPCs fell as a function of time, concomitant with the mitotic expansion and spread of donor hGPCs. By a year after neonatal xenograft, the forebrain GPC populations of implanted mice were largely, and often entirely, of human origin. Thus, neonatally implanted hGPCs outcompeted and ultimately replaced the host population of mouse GPCs, ultimately generating mice with a humanized glial progenitor population. These human glial chimeric mice should permit us to define the specific contributions of glia to a broad variety of neurological disorders, using human cells in vivo.
Assuntos
Quimera/fisiologia , Células-Tronco Fetais/fisiologia , Células-Tronco Fetais/transplante , Neuroglia/fisiologia , Neuroglia/transplante , Prosencéfalo/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Prosencéfalo/citologia , Transplante de Células-Tronco/métodosRESUMO
The diseases of myelin are among the most prevalent and disabling conditions in neurology. These diseases include both the vascular and inflammatory demyelinating disorders of adulthood, as well as the childhood leukodystrophies and cerebral palsy. These fundamentally glial disorders may be amenable to treatment by glial progenitor cells (GPCs), which give rise to astroglia and myelin-producing oligodendrocytes. Given the development of new methods for generating and isolating human GPCs, the myelin disorders may now be compelling targets for cell-based therapy. In addition, the efficient engraftment and expansion of human GPCs in murine hosts has led to the development of human glial chimeric mouse brains, which provides new opportunities for studying the species-specific roles of human glia in cognition, as well as in disease pathogenesis.
Assuntos
Doenças Desmielinizantes/terapia , Modelos Neurológicos , Células-Tronco Neurais/transplante , Oligodendroglia/transplante , Adulto , Animais , Criança , Quimera , Modelos Animais de Doenças , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Humanos , Camundongos , Bainha de Mielina/metabolismo , Células-Tronco Neurais/fisiologia , Oligodendroglia/metabolismo , Oligodendroglia/fisiologiaRESUMO
Experimental animals with myelin disorders can be treated by transplanting oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs have been isolated by their expression of gangliosides recognized by mAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we sorted fetal human forebrain cells for CD140a, an epitope of platelet derived growth factor receptor (PDGFR)α, which is differentially expressed by OPCs. CD140a(+) cells were isolated as mitotic bipotential progenitors that initially expressed neither mature neuronal nor astrocytic phenotypic markers, yet could be instructed to either oligodendrocyte or astrocyte fate in vitro. Transplanted CD140a(+) cells were highly migratory and robustly myelinated the hypomyelinated shiverer mouse brain more rapidly and efficiently than did A2B5(+)cells. Microarray analysis of CD140a(+) cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9(+)/CD140a(+) cells may constitute an even more highly enriched population of myelinogenic progenitor cells.
Assuntos
Movimento Celular , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/transplante , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Axônios/metabolismo , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Células-Tronco Fetais/citologia , Células-Tronco Fetais/metabolismo , Feto/citologia , Regulação da Expressão Gênica , Humanos , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Células-Tronco/metabolismo , Tetraspanina 29/metabolismoRESUMO
Vanishing white matter (VWM) disease is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B. It is a disease of infants, children, and adults who experience a slowly progressive neurologic deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathologic findings include cystic degeneration of the white matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, weinvestigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other white matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot, and quantitative polymerase chain reaction. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM. We also demonstrated a significant increase in numbers of premyelinating oligodendrocyte progenitors in VWM, which may explain the coexistence of oligodendrocytosis and myelin paucity in the patients' white matter.
Assuntos
Diferenciação Celular , Leucoencefalopatias/patologia , Fibras Nervosas Mielinizadas/patologia , Neuroglia/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular/fisiologia , Crescimento Celular , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Adulto JovemRESUMO
Glial progenitor cells (GPCs) comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for central nervous system (CNS) remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand-receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function.
Assuntos
Células-Tronco Adultas/fisiologia , Encéfalo/citologia , Diferenciação Celular/fisiologia , Neuroglia/fisiologia , Animais , Humanos , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologiaRESUMO
The pediatric leukodystrophies comprise a category of disease manifested by neonatal or childhood deficiencies in myelin production or maintenance; these may be due to hereditary defects in one or more genes critical to the initiation of myelination, as in Pelizaeus-Merzbacher Disease, or to enzymatic deficiencies with aberrant substrate accumulation-related dysfunction, as in the lysosomal storage disorders. Despite differences in both phenotype and natural history, these disorders are all essentially manifested by a profound deterioration in neurological function with age. A congenital deficit in forebrain myelination is also noted in children with the periventricular leukomalacia of cerebral palsy, another major source of neurological morbidity. In light of the wide range of disorders to which congenital hypomyelination and/or postnatal demyelination may contribute, and the relative homogeneity of central oligodendrocytes and their progenitors, the pediatric leukodystrophies may be especially attractive targets for cell-based therapeutic strategies. As a result, glial progenitor cells (GPCs), which can give rise to new myelinogenic oligodendrocytes, have become of great interest as potential therapeutic vectors for the restoration of myelin to the hypomyelinated or dysmyelinated childhood CNS. In addition, by distributing themselves throughout the deficient host neuraxis after perinatal allograft, and giving rise to astrocytes as well as oligodendrocytes, glial progenitors appear to be of potential great utility in rectifying enzymatic deficiencies. In this review, we focus on current efforts to develop the use of isolated human GPCs as transplantable agents both for mediating enzymatic restoration to the enzyme-deficient brain and for therapeutic myelination in the disorders of congenital hypomyelination.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Doenças Desmielinizantes/terapia , Bainha de Mielina/metabolismo , Transplante de Células-Tronco , Criança , Doenças Desmielinizantes/congênito , Doenças Desmielinizantes/imunologia , Humanos , Leucodistrofia de Células Globoides/imunologia , Leucodistrofia de Células Globoides/terapia , Doenças por Armazenamento dos Lisossomos/imunologia , Doenças por Armazenamento dos Lisossomos/terapia , Neuroglia/imunologia , Neuroglia/transplante , Células-Tronco/imunologiaRESUMO
Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal shiverer x rag2(-/-) mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
Assuntos
Células-Tronco Adultas/transplante , Corpo Caloso/transplante , Bainha de Mielina/metabolismo , Bainha de Mielina/transplante , Neuroglia/transplante , Transplante de Células-Tronco , Células-Tronco Adultas/metabolismo , Agenesia do Corpo Caloso , Animais , Animais Recém-Nascidos/anormalidades , Animais Recém-Nascidos/embriologia , Terapia Baseada em Transplante de Células e Tecidos , Corpo Caloso/embriologia , Corpo Caloso/metabolismo , Doenças Desmielinizantes/congênito , Doenças Desmielinizantes/terapia , Humanos , Hospedeiro Imunocomprometido , Camundongos , Bainha de Mielina/genética , Condução Nervosa , Neuroglia/metabolismo , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/transplante , Distribuição Tecidual , Quimeras de Transplante/embriologiaRESUMO
Diseases of the brain and spinal cord represent especially daunting challenges for cell-based strategies of repair, given the multiplicity of cell types within the adult central nervous system, and the precision with which they must interact in both space and time. Nonetheless, a number of diseases are especially appropriate for cell-based therapy, in particular those in which single phenotypes are lost, and in which the re-establishment of vectorially specific connections is not entirely requisite for therapeutic benefit. We review here a set of potential therapeutic indications that meet these criteria as potentially benefiting from the transplantation of neural stem and progenitor cells. These include: (i) transplantation of phenotypically restricted neuronal progenitor cells into diseases of a single neuronal phenotype, such as Parkinson's disease; (ii) implantation of mixed progenitor pools into diseases characterized by the loss of a limited number of discrete phenotypes, such as spinal cord injury and the motor neuronopathies; (iii) transplantation of glial and nominally oligodendrocytic progenitor cells as a means of treating disorders of myelin; and (iv) transplantation of neural stem cells as a means of treating lysosomal storage disorders and other diseases of enzymatic deficiency. Among the diseases potentially approachable by these strategies, the myelin disorders, including the paediatric leucodystrophies as well as adult traumatic and inflammatory demyelinations, may present the most compelling targets for cell-based neurological therapy.