RESUMO
In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.
Assuntos
Envelhecimento , Exossomos , Hipotálamo , MicroRNAs , Células-Tronco Neurais , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Exossomos/metabolismo , Hipotálamo/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Redes Reguladoras de Genes , Senescência Celular/genética , Encéfalo/metabolismo , Camundongos , Parabiose , Oligodendroglia/metabolismo , Transcriptoma , Regulação da Expressão Gênica , Perfilação da Expressão GênicaRESUMO
INTRODUCTION: The aim of this study was to analyze the contribution of nonresident progenitor/stem cells and hematopoietic cells to reparative dentinogenesis. METHODS: Parabiosis was established between C57BL/6-TgN(ACTbEGFP)10sb/J transgenic mice (GFP+) and C57BL/6 wild-type mice (GFP-) to ensure blood cross-circulation between animals. Reparative dentinogenesis was stimulated by pulp exposures and capping on the first maxillary molar in the GFP- mice. Histologic sections of injured molars from GFP- mice were analyzed by epifluorescence microscopy to examine the contributions of GFP+ cells (nonresident progenitor cells and hematopoietic cells originating from GFP+ mice) to reparative dentinogenesis. RESULTS: GFP+ cells were detected in close association with reparative dentin formed at the site of pulp exposure in the maxillary first molars of the GFP- mice. CONCLUSIONS: The present study suggests the participation of the nonresident progenitor cells and hematopoietic cells in reparative dentinogenesis.
Assuntos
Dentinogênese/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Parabiose/métodos , Células-Tronco/fisiologia , Fosfatase Ácida/análise , Compostos de Alumínio/uso terapêutico , Animais , Biomarcadores/análise , Compostos de Cálcio/uso terapêutico , Resinas Compostas/química , Circulação Cruzada/métodos , Materiais Dentários/química , Capeamento da Polpa Dentária/métodos , Exposição da Polpa Dentária/patologia , Exposição da Polpa Dentária/terapia , Dentina Secundária/fisiologia , Combinação de Medicamentos , Citometria de Fluxo , Corantes Fluorescentes , Proteínas de Fluorescência Verde , Isoenzimas/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência , Modelos Animais , Dente Molar/patologia , Dente Molar/fisiopatologia , Odontoblastos/patologia , Óxidos/uso terapêutico , Agentes de Capeamento da Polpa Dentária e Pulpectomia/uso terapêutico , Cimentos de Resina/química , Silicatos/uso terapêutico , Dióxido de Silício/química , Fosfatase Ácida Resistente a Tartarato , Zircônio/químicaRESUMO
Correlacionando teorias, discutiremos aspectos da Homeopatia no sentido de mostrar a importancia de dar-lhe uma base teorica cientificae, como os ensinamentos da neurofisiologia cortico-visceral de Pavlov podem lhe ser uteis, principalmente na explicacao do modo de acao dos medicamentos homeopaticos no organismo
Assuntos
Farmacodinâmica do Medicamento Homeopático , Neurofisiologia , ParabioseRESUMO
Correlacionando teorias, discutiremos aspectos da Homeopatia no sentido de mostrar a importancia de dar-lhe uma base teorica cientificae, como os ensinamentos da neurofisiologia cortico-visceral de Pavlov podem lhe ser uteis, principalmente na explicacao do modo de acao dos medicamentos homeopaticos no organismo
Assuntos
Neurofisiologia , Farmacodinâmica do Medicamento Homeopático , ParabioseRESUMO
In the Mexican axolotl, Ambystoma mexicanum, the developmental mutation lethal t is inherited as a simple Mendelian recessive. Mutant larvae failed to feed and died, on the average, 17 days after hatching. Unfed wild-type larvae died an average of 23 days after hatching. By 15 days, forelimb development had progressed further in the wild type; a cartilaginous scapula and humerus were present, but no cartilage was seen in the mutant limb. Histological examination indicated that the visceral cartilage may also be abnormal, and the rectus cervicus muscle was found to have fewer and smaller fibers. Though the mutant was not rescued by parabiosis with wild-type embryos, transplants of presumptive gill and limb tissue to wild-type hosts survived, indicating that the mutation is not an autonomous cell lethal.
Assuntos
Ambystoma/genética , Animais , Cartilagem/embriologia , Comportamento Alimentar , Genes Letais , Genes Recessivos , Larva , ParabioseAssuntos
Antígenos de Helmintos/imunologia , Parabiose , Schistosoma mansoni/imunologia , Esquistossomose/imunologia , Animais , Granuloma/parasitologia , Intestinos/patologia , Fígado/patologia , Hepatopatias Parasitárias/imunologia , Fatores Inibidores da Migração de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Baço/patologia , Linfócitos T/imunologiaRESUMO
Cell-lethal developmental mutations, which are presumed to affect the viability of all cells in a mutant embryo, have been distinguished from other development lethals on the basis of the results of parabiosis and transplant experiments. Premature death (p), previously classified as a cell lethal, does not survive parabiosis. However, transplants involving mutant eye, flank epidermis and primordial limb tissue all survived on a normal recipient. The mutant, therefore, cannot be considered a true cell lethal, though it suffers from serious and widespread abnormalities that cannot be corrected by parabiosis. In addition, transplants of mutant branchial mound tissue did not develop into normal gills on a normal recipient. These transplants were the only ones involving mutant endoderm, and their failure supports our hypothesis that the mutation leads to a specific endoderm defect.
Assuntos
Ambystoma mexicanum/embriologia , Ambystoma/embriologia , Genes Letais , Mutação , Ambystoma mexicanum/genética , Animais , Extremidades/transplante , Olho/transplante , Brânquias/transplante , ParabioseAssuntos
Ambystoma/genética , Genes Recessivos , Animais , Membro Anterior/transplante , Genes Letais , Genótipo , Brânquias/transplante , Homozigoto , Larva , Mutação , Parabiose , Fenótipo , Transplante HomólogoRESUMO
Three mutant genes, st, mi, and h, were discovered in an axolotl male received from Mexico City. All three are recessive to their normal alleles, and appear to segregate independently. Larvae homozygous for st (for stasis) suffer blockage of the circulation at hatching or shortly after, and the majority soon die; any surviving live only a few weeks at most. The mi/mi (microphthalmic) can be identified at the feeding stage. None survives more than a few days. The h/h (hand lethals) live until the digits have appeared on the forelimb. They may then be recognized by the thumb-like orientation of digit 1. Transplants from st/st embryos into normal produce normal structures which persist indefinitely. Those from mi/mi and h/h donors do not survive. The structures (forelimb, gills) derived from h/h donors grow for a relatively long time, and their final death and degeneration result in defects leading to death of most of the recipients. Parabiosis is of no benefit to st/st or h/h mutants and leads to the death of the normal twin; mi/mi mutants undergo a gradual absorption by the normal twin.
Assuntos
Ambystoma/genética , Genes Letais , Genes Recessivos , Mutação , Animais , Circulação Sanguínea , Feminino , Membro Anterior/anormalidades , Membro Anterior/transplante , Masculino , Microftalmia , Parabiose , Transplante HomólogoRESUMO
The premature death (p) mutation is a recessive lethal, which, in the homozygous condition, gives rise to a complex of abnormalities. The mutant embryos develop only to stage 37, at which time disintegration of superficial tissue begins. Many of the abnormalities observed in sections of the stage-37 mutant embryo are related to its failure to establish a functioning circulatory system, or to the resulting edema and/or ascites that distend the abdomen and flanks. There are, however, abnormalities of heart, liver, gill and muscle development which cannot be attributed to lack of circulation and edema. All of these abnormalities can be indirectly related to the endoderm, particularly the anterior and dorsal endoderm. The findings, therefore, suggest that the mutation leads to a fairly general defect of the endoderm.
Assuntos
Ambystoma/embriologia , Genes Letais , Mutação , Animais , Endoderma/anatomia & histologia , Genes Recessivos , Brânquias/anormalidades , Ventrículos do Coração/anormalidades , Intestinos/anormalidades , Fígado/anormalidades , ParabioseRESUMO
1. Gene l is a recessive lethal factor found in the white strain of axolotls. Animals heterozygous for the gene are phenotypically normal. When mated with each other they give offspring 25% of which exhibit the lethal effects of the gene. 2. The l/l homozygotes develop normally to an advanced embryonic stage (Harrison stage 40) before the effects of the gene are first manifested. They then come to display a characteristic combination of abnormalities, including a disproportionately small head, small and poorly developed eyes, abnormal poorly developed gills, undifferentiated limb buds, and reduced overall growth rate. They may feed briefly, but soon stop and invariably die within a few weeks of the time of hatching. 3. The action of gene l has been analyzed by parabiosing mutant and normal embryos, and by grafting various organ primordia reciprocally between mutant and normal embryos. Parabiosis to normal embryos fails to correct the abnormalities of the mutants, although their survival may be somewhat prolonged. Grafts of mutant organ primordia (eye, limb, gill, pronephros, gonad, head) also invariably fail to show improved development or to survive on normal hosts; normal organ primordia develop normally on mutant hosts so long as the mutant survives. These experiments indicate that gene l is a recessive autonomous cell lethal affecting all of the organ systems during late embryonic and early larval development.