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Impact of sustained TGFβ-receptor inhibition on chromatin accessibility and gene expression in cultured endometrial MSC [ATAC-Seq]

ABSTRACT: 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 TGFbeta receptor inhibitor, promotes pharmacological expansion of eMSC in culture by blocking differentiation and senescence. We subjected primary eMSC treated with A83-01 to 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. ATAC-seq analysis demonstrated that sustained TGFbeta-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146065 | GEO | 2020/09/23

REPOSITORIES: GEO

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Impact of sustained TGFβ-receptor inhibition on chromatin accessibility and gene expression in cultured endometrial MSC [RNA-Seq]

Project description: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 TGFbeta receptor inhibitor, promotes pharmacological expansion of eMSC in culture by blocking differentiation and senescence. We subjected primary eMSC treated with A83-01 to RNA sequencing (RNA-seq) to map the underlying gene expression changes. RNA-seq analysis demonstrated that sustained TGFbeta-R inhibition results in differential expression of 1,463 genes.

2020-09-23 | GSE146066 | GEO

The transcriptome of human endometrial mesenchymal stem cells under TGFβR inhibition reveals improved potential for cell-based therapies

Project description:Mesenchymal stem/stromal cells (MSCs) are multipotent cells with favorable properties for cell therapy and regenerative medicine. Human endometrium harbors a small population of perivascular, clonogenic MSCs (eMSCs) identified by the SUSD2 marker. As for other MSCs, eMSCs require extensive in vitro expansion to generate clinically relevant numbers of cells, resulting in spontaneous differentiation, replicative senescence, and cell death, decreasing therapeutic potency. We previously demonstrated that A83-01, a TGF-b receptor inhibitor maintained eMSCs clonogenicity, promoted proliferation, prevented apoptosis and maintained MSC function in vitro. Here we compare the transcriptome of passaged eMSCs from six women cultured with and without A83-01 for 7 days. We identified 1206 differentially expressed genes using a false discovery rate cut-off at 0.01 and fold change >2. Significant enrichment of genes involved in inflammatory responses, angiogenesis, cell migration and proliferation, and reduced smooth muscle proliferation, collagen fibril and extracellular matrix organization genes were revealed. TGF-b, Wnt and Akt signaling pathways were decreased. Anti-fibrotic and anti-apoptotic genes were induced, and fibroblast proliferation and myofibroblast related genes were down-regulated. We validated the enhanced potency of A83-01-treated eMSCs and found increased MSC potency genes (TWIST1, TWIST2, JAG1, LIFR, and SLIT2) and no pluripotency gene expression. Increased angiogenic capacity was functionally demonstrated in vitro, and our angiogenic and cytokine protein arrays further confirmed the angiogenic, antifibrotic and immunomodulatory phenotype of A83-01-treated eMSCs. Overall, we showed that eMSCs culture expanded with A83-01 have improved potential for cell-therapies and regenerative medicine applications.

2018-12-19 | GSE115137 | GEO

Analysis of transcriptomes during cardioac reprogramming by RNA-deep Sequencing

Project description:Fibroblasts can be reprogrammed into cardiomyocyte-like cells by overexpressing transcription factors, GATA4, Hand2, Mef2C and Tbx5 (GHMT). A83-01, an inhibitor of ALK4, ALK5 and ALK7 and two microRNA, miR-1 and miR-133 increase the efficiency of cardiac reprogramming. RNA_Seq was performed to anyalyze effects of these factors on gene expression. Total RNAs were prepared from mouse embryonic fibroblasts (MEFs); Reprogramming fibroblasts including MEFs transduced with retroviruses encoding GHMT, MEFs transduced with with retroviruses encoding GHMT plus miR-1 and miR-133 (GHMT2m), MEFs transduced with with retroviruses encoding GHMT2m treated with A83-01, at day 7 after viral transduction; and neonatal mouse cardiomyocytes (NMCMs).

2015-07-28 | E-GEOD-71405 | biostudies-arrayexpress

Analysis of chromatin accessibility in decidualizing human endometrial stromal cells

Project description: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 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 1,533 opening as well as closing chromatin regions revealed overrepresentation 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 (bZIP), 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, suggesting a role for this primate-specific transposable element (TE) in the evolution of decidual genes. Although other TEs were generally underrepresented in open chromatin of undifferentiated EnSCs, several classes contributed to the regulatory DNA landscape that underpins decidual gene expression.

2018-02-28 | GSE104720 | GEO

Long-term maintenance of functional primary human hepatocytes using small molecules

Project description:Primary human hepatocytes (PHHs) were cultured with or without a cocktail of four small molecules, Y-27632, PD0325901, A83-01 and CHIR99021 (termed YPAC), and their transcriptomes after a long-trm culture were compared.

2019-09-01 | GSE135011 | GEO

Impacts of reprogramming method and culture conditions in trophoblast differentiation of induced pluripotent stem cells

Project description:Trophoblast differentiation from human ESC has been achieved by exposing the cells to BMP4 with or without supplementation of ALK4/5/7 inhibitor (A83-01) and FGF2 signaling inhibitor (PD173074) (BAP). Here the two differentiation conditions, BMP4 and BAP were applied to two sets of human PSC lines, H1 ESC and iPSC that latter was generated by DOX-inducible lentiviral (V) transductions of umbilical cord mesenchymal cells. The V-iPSC showed residual transgene expressions from the viral vectors in DOX-free culture condition. When the both ESC and iPSC lines were differentiated simultaneously, similar time dependent morphological changes were observed but BMP4 treated V-iPSC showed a minor yet consistent lag in the differentiation progression compared to BMP4 treated hESC. Although both differentiated ESC and V-iPSC showed dominant trophoblast phenotypes, the BMP4 treated V-iPSC also expressed gene markers consistent with the presence of mesoendoderm. The BAP condition provided more efficient differentiation than BMP4 alone, and the BAP-differentiated iPSC and ESC never expressed mesoendoderm markers. Five samples, one control of undifferentiated V-iPSC (FGF2) and four differentiated samples included two H1 ESC (treated with BMP4 or BMP4+A83-01) and similarly treated two V-iPSC were analyzed. Trophoblast differentiation was conducted with BMP4 (10 ng/ml) with or without supplementation of ALK4/5/7 inhibitor (A83-01; 1 μM) to H1 ESC and V-iPSC, respective reagents were added to FGF2-free MEF-CM from the second day culture of following passages for up to six additional days.

2015-08-31 | E-GEOD-64272 | biostudies-arrayexpress

ISRIB can temporarily maintain the cell fate of human trophoblast stem cell without activating WNT and inhibiting TGFβ

Project description:To investigate the role of ISRIB in human trophoblast stem cell(hTSC) maintenance without activation of WNT & TGFβ. We performed gene expression profiling analysis using data obtained from RNA-seq of hTSCs cultured in the medium contained 0.5 µM ISRIB and 10 µM Y27652, after removing CHIR99021, A83-01, SB431542.

2023-12-31 | GSE221409 | GEO

Analysis of transcriptomes during cardioac reprogramming by RNA-deep Sequencing

2015-07-28 | GSE71405 | GEO

Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells

Project description:Currently, much effort is directed to the development of new cell sources for clinical therapy using cell fate conversion approaches by small molecules. Direct lineage reprogramming to a progenitor state has been reported in terminally differentiated rodent hepatocytes, yet remains a challenge in human hepatocytes. Human hepatocytes were isolated from healthy and diseased donor livers and reprogrammed into progenitor cells by two small molecules, A83-01 and CHIR99021 (AC), in the presence of EGF and HGF. The stemness properties of human chemically derived hepatic progenitors (hCdHs) were tested by standard in vitro and in vivo assays and transcriptome profiling. We developed a robust culture system for generating hCdHs with therapeutic potential. The use of HGF proved to be an essential determinant of fate conversion process. Based on functional evidence, activation of HGF/MET signal transduction system collaborated with A83-01 and CHIR99021 to allow a rapid expansion of progenitor cells through activation of ERK pathway. hCdHs expressed hepatic progenitor marker genes and proteins, and could self-renew for at least 10 passages while retaining normal karyotype and potential to differentiate into functional hepatocytes and biliary epithelial cells in vitro. RNASeq gene expression profiling confirmed transcriptional reprogramming of hCdHs toward a progenitor state and suppression of mature hepatocyte transcripts. Upon intrasplenic transplantation into immunocompromised mice with acute liver injury, hCdHs effectively repopulated damaged parenchyma. Our study is a first report of successful reprogramming of human hepatocytes to a population of proliferating bipotent cells with regenerative potential. hCdHs may provide a nove tool that permits expansion and genetic manipulation of patient-specific progenitors to study regeneration and repair of diseased liver.

2019-05-08 | GSE114643 | GEO

Delamination of trophoblast-like syncytia from the amniotic ectodermal analogue in human primed embryonic stem cell-based differentiation model [RNA-seq]

Project description:Human embryonic stem cells were converted into GATA3-expressing extraembryonic cells (GATA3+ ExE cells) when they were exposed to chemical inhibitors for ACTIVIN/NODAL (A83-01, 1uM) and FGF signaling (PD03714, 100nM). We refer here to this inhibitor-induced differentiation method as an 'AP' protocol. To understand the transcriptome dynamics during AP-induced differentiation, we performed timecourse profiling of genome-wide gene expression by RNA sequencing.

2022-06-21 | GSE175977 | GEO

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