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1.
Nat Rev Neurol ; 19(7): 434-443, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37268723

RESUMO

Most age-related neurodegenerative diseases remain incurable owing to an incomplete understanding of the disease mechanisms. Several environmental and genetic factors contribute to disease onset, with human biological ageing being the primary risk factor. In response to acute cellular damage and external stimuli, somatic cells undergo state shifts characterized by temporal changes in their structure and function that increase their resilience, repair cellular damage, and lead to their mobilization to counteract the pathology. This basic cell biological principle also applies to human brain cells, including mature neurons that upregulate developmental features such as cell cycle markers or glycolytic reprogramming in response to stress. Although such temporary state shifts are required to sustain the function and resilience of the young human brain, excessive state shifts in the aged brain might result in terminal fate loss of neurons and glia, characterized by a permanent change in cell identity. Here, we offer a new perspective on the roles of cell states in sustaining health and counteracting disease, and we examine how cellular ageing might set the stage for pathological fate loss and neurodegeneration. A better understanding of neuronal state and fate shifts might provide the means for a controlled manipulation of cell fate to promote brain resilience and repair.


Assuntos
Doenças Neurodegenerativas , Neurônios , Humanos , Idoso , Neurônios/fisiologia , Neuroglia/metabolismo , Encéfalo , Doenças Neurodegenerativas/metabolismo , Envelhecimento
2.
Cell Stem Cell ; 28(9): 1533-1548.e6, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33910058

RESUMO

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Idoso , Envelhecimento , Fibroblastos , Humanos , Neurônios
3.
Front Cell Dev Biol ; 8: 567610, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984350

RESUMO

Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-ß receptor (TGFß-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFß-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFß-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RARß). Selective RARß inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.

4.
FASEB J ; 32(5): 2467-2477, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29259032

RESUMO

Spontaneous decidualization of the endometrium in response to progesterone signaling is confined to menstruating species, including humans and other higher primates. During this process, endometrial stromal cells (EnSCs) differentiate into specialized decidual cells that control embryo implantation. We subjected undifferentiated and decidualizing human EnSCs to an assay for transposase accessible chromatin with sequencing (ATAC-seq) to map the underlying chromatin changes. A total of 185,084 open DNA loci were mapped accurately in EnSCs. Altered chromatin accessibility upon decidualization was strongly associated with differential gene expression. Analysis of 1533 opening and closing chromatin regions revealed over-representation of DNA binding motifs for known decidual transcription factors (TFs) and identified putative new regulators. ATAC-seq footprint analysis provided evidence of TF binding at specific motifs. One of the largest footprints involved the most enriched motif-basic leucine zipper-as part of a triple motif that also comprised the estrogen receptor and Pax domain binding sites. Without exception, triple motifs were located within Alu elements, which suggests a role for this primate-specific transposable element (TE) in the evolution of decidual genes. Although other TEs were generally under-represented in open chromatin of undifferentiated EnSCs, several classes contributed to the regulatory DNA landscape that underpins decidual gene expression.-Vrljicak, P., Lucas, E. S., Lansdowne, L., Lucciola, R., Muter, J., Dyer, N. P., Brosens, J. J., Ott, S. Analysis of chromatin accessibility in decidualizing human endometrial stromal cells.


Assuntos
Elementos Alu/fisiologia , Diferenciação Celular/fisiologia , Cromatina/metabolismo , Decídua/metabolismo , Regulação da Expressão Gênica/fisiologia , Loci Gênicos , Cromatina/genética , Decídua/citologia , Implantação do Embrião/fisiologia , Feminino , Humanos , Células Estromais/citologia , Células Estromais/metabolismo
5.
Elife ; 62017 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-29227245

RESUMO

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.


Assuntos
Senescência Celular , Decídua/citologia , Endométrio/citologia , Células Matadoras Naturais/citologia , Células Estromais/citologia , Útero/citologia , Diferenciação Celular , Células Cultivadas , Decídua/metabolismo , Endométrio/metabolismo , Feminino , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-15/metabolismo , Interleucina-8/metabolismo , Células Matadoras Naturais/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Útero/metabolismo
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