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Tissue- and Aging-specific DNA-Methylation Patterns are erased in Mesenchymal Stromal Cells derived from Induced Pluripotent Stem Cells. [Expression profiling]

ABSTRACT: Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate towards a ground-state and may therefore give rise to more standardized cell preparations. We reprogrammed bone marrow MSCs into iPSCs which were subsequently re-differentiated towards MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. DNA methylation (DNAm) profiles of iPSCs maintained some donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs and MSCs are similar in function but differ in their epigenetic makeup.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54766 | GEO | 2014/09/24

SECONDARY ACCESSION(S): PRJNA237584

REPOSITORIES: GEO

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Tissue- and Aging-specific DNA-Methylation Patterns are erased in Mesenchymal Stromal Cells derived from Induced Pluripotent Stem Cells. [Expression profiling]

Project description:Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate towards a ground-state and may therefore give rise to more standardized cell preparations. We reprogrammed bone marrow MSCs into iPSCs which were subsequently re-differentiated towards MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. DNA methylation (DNAm) profiles of iPSCs maintained some donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs and MSCs are similar in function but differ in their epigenetic makeup. 8 samples were hybridized to the GeneChip Human Gene 1.0 ST Array (Affymetrix)

2014-09-24 | E-GEOD-54766 | biostudies-arrayexpress

Tissue- and Aging-specific DNA-Methylation Patterns are erased in Mesenchymal Stromal Cells derived from Induced Pluripotent Stem Cells. [Methylation profiling]

Project description:Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate towards a ground-state and may therefore give rise to more standardized cell preparations. We reprogrammed bone marrow MSCs into iPSCs which were subsequently re-differentiated towards MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. DNA methylation (DNAm) profiles of iPSCs maintained some donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs and MSCs are similar in function but differ in their epigenetic makeup. 12 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip

2014-09-24 | E-GEOD-54767 | biostudies-arrayexpress

Tissue- and Aging-specific DNA-Methylation Patterns are erased in Mesenchymal Stromal Cells derived from Induced Pluripotent Stem Cells. [Methylation profiling]

2014-09-24 | GSE54767 | GEO

DNA methylation profiles of human umbilical vein endothelial cells (HUVECs)

Project description:Replicative senescence has major impact on function and integrity of cell preparations. DNA-methylation (DNAm) changes are continuously acquired at specific CpG dinucleotides during in vitro culture. Such modifications can be used to estimate the state of cellular senescence for quality control of cell preparations. It is however unclear how senescence-associated DNAm changes are regulated and if they occur simultaneously throughout cell populations. In this study, we analyzed global DNAm profiles of human mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVEC) to demonstrate that senescence-associated DNAm changes are overall similar in these different cell types. Subsequently, an Epigenetic-Senescence-Signature, based on six CpGs, was either analyzed by pyrosequencing or by barcoded bisulfite amplicon sequencing. There was a good correlation between predicted and real passage numbers in bulk populations of MSCs (R² = 0.67) and HUVECs (R² = 0.97).

2017-02-20 | GSE82234 | GEO

Interrupted reprogramming into induced pluripotent stem cells does not rejuvenate human mesenchymal stromal cells

Project description:Replicative senescence hampers application of mesenchymal stromal cells (MSCs) because it limits culture expansion, impairs differentiation potential, and hinders reliable standardization of cell products. MSCs can be rejuvenated by reprogramming into induced pluripotent stem cells (iPSCs), which is associated with complete erasure of age- and senescence-associated DNA methylation (DNAm) patterns. However, this process is also associated with erasure of cell-type and tissue-specific epigenetic characteristics that are not recapitulated upon re-differentiation towards MSCs. In this study, we therefore followed the hypothesis that overexpression of pluripotency factors under culture conditions that do not allow full reprogramming might reset senescence-associated changes without entering a pluripotent state. MSCs were transfected with episomal plasmids and either successfully reprogrammed into iPSCs or cultured in different media with continuous passaging every week. Overexpression of pluripotency factors without reprogramming did neither prolong culture expansion nor ameliorate molecular and epigenetic hallmarks of senescence. Notably, transfection resulted in immortalization of one cell preparation with gain of large parts of the long arm of chromosome 1. Taken together, premature termination of reprogramming does not result in rejuvenation of MSCs and harbours the risk of transformation. This approach is therefore not suitable to rejuvenate cells for cellular therapy.

2019-05-21 | GSE115666 | GEO

Matrix Elasticity Does Not Affect Replicative Senescence or DNA Methylation Patterns of Mesenchymal Stem Cells [gene expression profiling]

Project description:Matrix elasticity influences differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient - while the cells reside on the substrate - or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on polydimethylsiloxane (PDMS) gels of different elasticity or on tissue culture plastic (TCP) to compare impact on replicative senescence, in vitro differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively - but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate. Our results support the notion that matrix elasticity influences cellular differentiation while the cells are organized on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns. MSCs cultivated either on polydimethylsiloxane (PDMS) gels of different elasticity or on tissue culture plastic (TCP) to compare impact on gene expression profiles.

2014-07-29 | E-GEOD-55867 | biostudies-arrayexpress

Matrix Elasticity Does Not Affect Replicative Senescence or DNA Methylation Patterns of Mesenchymal Stem Cells [DNAm profiling]

Project description:Matrix elasticity influences differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient - while the cells reside on the substrate - or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on polydimethylsiloxane (PDMS) gels of different elasticity or on tissue culture plastic (TCP) to compare impact on replicative senescence, in vitro differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively - but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate (hPL-gel). Our results support the notion that matrix elasticity influences cellular differentiation while the cells are organized on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns. 20 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip

2014-07-29 | E-GEOD-55888 | biostudies-arrayexpress

Tracking of epigenetic changes during hematopoietic differentiation of induced pluripotent stem cells

Project description:Differentiation of induced pluripotent stem cells (iPSCs) toward hematopoietic progenitor cells (HPCs) raises high hopes for disease modelling, drug screening, and cellular therapy. Various differentiation protocols have been established to generate iPSC-derived HPCs (iHPCs) that resemble their primary counterparts in morphology and immunophenotype, whereas a systematic epigenetic comparison was yet elusive. In this study, we compared genome wide DNA methylation (DNAm) patterns of iHPCs with various different hematopoietic subsets. Furthermore, we analyzed if additional co-culture for two weeks with syngenic primary mesenchymal stromal cells (MSCs) or iPSC-derived MSCs (iMSCs) further supports epigenetic maturation toward hematopoietic lineage. After 20 days of in vitro differentiation cells revealed typical hematopoietic morphology, CD45 expression and colony forming unit (CFU) potential. DNAm changes were particularly observed in genes that are associated with hematopoietic differentiation. On the other hand, the epigenetic profiles of iHPCs remained overall very distinct from normal hematopoiesis. Co-culture with MSCs or iMSCs enhanced proliferation of iHPCs and maintenance of CFU potential. However, morphology, immunophenotype, and DNAm profiles did not indicate that additional culture expansion with stromal support increases hematopoietic differentiation. In conclusion, differentiation of iPSCs towards hematopoietic lineage remains epigenetically incomplete. These results substantiate the need to elaborate advanced differentiation regimen while DNAm profiles provide a suitable measure to track this process.

2019-01-24 | GSE119079 | GEO

Epigenetic drift during long-term culture of cells in vitro

Project description:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes These changes might be directly regulated or caused by gradual deregulation of the epigenetic state, which is often referred to as “epigenetic drift” We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types During reprogramming into induced pluripotent stem cells (iPSCs) particularly the culture-associated hypomethylation is reversed simultaneously with age-associated and pluripotency-associated DNAm changes Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpolulations of MSCs at later passages Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF Taken together, our results indicate that DNAm changes during culture-expansion resembles epigenetic drift

2021-05-26 | GSE116375 | GEO

Epigenetic drift during long-term culture of cells in vitro [4C]

Project description:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes. These changes might be directly regulated or caused by gradual deregulation of the epigenetic state, which is often referred to as “epigenetic drift”. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. During reprogramming into induced pluripotent stem cells (iPSCs) particularly the culture-associated hypomethylation is reversed simultaneously with age-associated and pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpolulations of MSCs at later passages. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, our results indicate that DNAm changes during culture-expansion resembles epigenetic drift.

2021-05-26 | GSE165603 | GEO

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