Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA138165 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice
2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress
Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors.
2011-05-06 | GSE27686 | GEO
Project description:The premature aging disorder Werner Syndrome (WS) is characterized by early onset of aging phenotypes resembling natural aging. In most WS patients there are mutations in the DNA helicase WRN, an enzyme important in maintaining genome stability and telomere replication. Interestingly, its clinical manifestations reflect a severe degree of deterioration for connective tissue, whereas the central nervous system is less affected. We suggest that the varied vulnerability to aging is regulated by an unknown mechanism that protects specific lineages of stem cells from premature senescence. To address this problem, we reprogrammed patient skin fibroblasts to induced pluripotent stem cells (iPSC). The expression profile for the differentiated normal and WS fibroblasts and undifferentiated iPSC were compared. A distinct expression profile was found between normal and WS fibroblasts, however, few changes of gene expression were found in iPSC. Our findings suggest an erasure of aging phenotype associated with WS in reprogrammed iPSC. Human normal and WS skin fibroblasts were reprogrammed to induced pluripotent stem cells (iPSC). These samples, before and after reprogramming, were analyzed for the change of gene expression profile.
2013-07-11 | E-GEOD-48761 | biostudies-arrayexpress
Project description:The premature aging disorder Werner Syndrome (WS) is characterized by early onset of aging phenotypes resembling natural aging. In most WS patients there are mutations in the DNA helicase WRN, an enzyme important in maintaining genome stability and telomere replication. Interestingly, its clinical manifestations reflect a severe degree of deterioration for connective tissue, whereas the central nervous system is less affected. We suggest that the varied vulnerability to aging is regulated by an unknown mechanism that protects specific lineages of stem cells from premature senescence. To address this problem, we reprogrammed patient skin fibroblasts to induced pluripotent stem cells (iPSC). The expression profile for the differentiated normal and WS fibroblasts and undifferentiated iPSC were compared. A distinct expression profile was found between normal and WS fibroblasts, however, few changes of gene expression were found in iPSC. Our findings suggest an erasure of aging phenotype associated with WS in reprogrammed iPSC.
2013-07-11 | GSE48761 | GEO
Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.
2020-08-31 | GSE141107 | GEO
Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.
2020-08-31 | GSE141106 | GEO
Project description:Zmpste24 is a metalloproteinase processing prelamin A into mature lamin A, a nuclear structure protein. Zmpste24-/- mice which accumulate prelamin A in cells recapitulate accelerated aging phenotypes observed in human premature aging disorder, Hutchinson Gilford progeria sydrome (HGPS). Zmpste24-/- mouse embryonic fibroblasts (MEFs) exhibited genomic instabiliy and accelerated aging at cellular level, which is premature senescence. We performed microarray analysis on Zmpste24-/- MEFs, compared to wild-type littermates' MEFs, at an early passage (P3), which is a pre-symptom stage before cellular senescence occurs in the mutant MEFs, in order to examine gene expression profile and figure out the underneath mechanism triggering the premature aging process. Early passage wild-type and Zmpste24-/- MEFs were collected for RNA extraction, the quality of RNAs were determinded by Electrophoresis Assay (2100 Bioanalyzer, Agilent) and RNA extractions were used for hybridization on Affymetrix microarrays.
2010-11-11 | E-GEOD-25257 | biostudies-arrayexpress
Project description:Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.
2023-10-12 | PXD036075 | Pride
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC
2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress
Project description:Aging of hematopoietic stem cells (HSCs) is associated with the decline of their regenerative capacity, and multi-lineage differentiation potential, contributing to development of blood disorders. The bone marrow microenvironment was recently suggested to influence HSC aging, however the underlying mechanisms remain largely unknown. Here, we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as premature loss of SNS nerves or adrenoreceptor b3 (ADRb3) signaling in the microenvironment accelerated the appearance of HSC aging phenotypes reminiscent of physiological aging. Strikingly, supplementation of ADRb3 sympathomimetics to old mice significantly rejuvenated in vivo function of old HSCs, suggesting that the preservation or restitution of SNS innervation during aging may hold the potential for novel HSC rejuvenation strategies.
2018-05-01 | GSE109546 | GEO