Genomic differences in fibroblasts, iPSC, iMSC and mesenchymal stem cells in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222324 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:Comparison of gene expression profiles of canine induced pluripotent stem cells (iPSC) and iPS derived mesenchymal stem cells (iMSC) by microarray Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from adipose or bone marrow tissues from younger donors, in part due to ease of procurement and to the superior immune modulatory activity of young MSC. However, use of MSC from multiple unrelated donors makes it difficult to standardize MSC cellular products with uniform immune modulatory properties. One solution to this problem is the use of MSC derived from induced pluripotent stem cells (iPSC), as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including their immune modulatory properties and their potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype even after multiple passages, did not form teratomas when inoculated in immune deficient mice, and did not induce tumor formation in purpose-bred dogs following systemic injection. The immune potency of iMSC was similar to that of adipose and bone-marrow derived MSC with respect to suppression of T cell and DC activation. We concluded therefore that iMSC were phenotypically stable, immunologically potent, and safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders.
2017-01-26 | GSE94081 | GEO
Project description:Genomic differences in fibroblasts, iPSC, iMSC and mesenchymal stem cells in mice
| PRJNA919176 | ENA
Project description:Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is an epigenetic phenomenon. It has been suggested that iPSC retain some tissue-specific memory whereas little is known about inter-individual epigenetic variation of iPSC clones. In this study we have reprogrammed mesenchymal stromal cells (MSC) from human bone marrow by retrovirus-mediated overexpression of OCT-3/4, SOX2, c-MYC, and KLF4. Global DNA-methylation profiles of the initial MSC, MSC-derived iPSC (iP-MSC) and embryonic stem cells (ESC) were then compared using a high density DNA-methylation array covering more than 450,000 CpG sites. Overall, DNA-methylation patterns of iP-MSC and ESC were similar whereas some CpG sites revealed highly significant differences, which were not related to parental MSC. Furthermore, hypermethylation in iP-MSC versus ESC was particularly enriched in developmental genes as well as shore regions next to CpG islands indicating that these differences are not due to tissue-specific memory or random de novo methylation. Subsequently, we searched for CpG sites with donor-specific variation in MSC preparations. These “epigenetic fingerprints” were highly enriched in non-promoter regions and outside of CpG islands – and they were maintained upon reprogramming into iP-MSC. In conclusion, DNA methylation profiles of iP-MSC clones from the same donor were closely related despite heterogeneity of MSC. On the other hand, iP-MSC maintain donor-derived epigenetic differences. In the absence of isogenic controls for disease modeling applications, it would therefore be more appropriate to compare iPSC from different donors rather than a high number of different clones from the same patient. 16 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip
2013-01-09 | E-GEOD-34688 | biostudies-arrayexpress
Project description:Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is an epigenetic phenomenon. It has been suggested that iPSC retain some tissue-specific memory whereas little is known about inter-individual epigenetic variation of iPSC clones. In this study we have reprogrammed mesenchymal stromal cells (MSC) from human bone marrow by retrovirus-mediated overexpression of OCT-3/4, SOX2, c-MYC, and KLF4. Global DNA-methylation profiles of the initial MSC, MSC-derived iPSC (iP-MSC) and embryonic stem cells (ESC) were then compared using a high density DNA-methylation array covering more than 450,000 CpG sites. Overall, DNA-methylation patterns of iP-MSC and ESC were similar whereas some CpG sites revealed highly significant differences, which were not related to parental MSC. Furthermore, hypermethylation in iP-MSC versus ESC was particularly enriched in developmental genes as well as shore regions next to CpG islands indicating that these differences are not due to tissue-specific memory or random de novo methylation. Subsequently, we searched for CpG sites with donor-specific variation in MSC preparations. These “epigenetic fingerprints” were highly enriched in non-promoter regions and outside of CpG islands – and they were maintained upon reprogramming into iP-MSC. In conclusion, DNA methylation profiles of iP-MSC clones from the same donor were closely related despite heterogeneity of MSC. On the other hand, iP-MSC maintain donor-derived epigenetic differences. In the absence of isogenic controls for disease modeling applications, it would therefore be more appropriate to compare iPSC from different donors rather than a high number of different clones from the same patient.
2013-01-09 | GSE34688 | GEO
Project description:Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, andpremature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC(iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.
2024-08-26 | GSE271374 | GEO
Project description:Yamanaka reprogramming is revolutionary but inefficient, slow and stochastic. The underlying molecular events for these mixed outcomes of iPSC reprogramming is still unclear. Previous studies about transcriptional responses to reprogramming overlooked human reprogramming, and are compromised by the fact that only a rare population proceeds towards pluripotency and a significant amount of the collected transcriptional data may not represent the positive reprogramming. We recently developed a concept of reprogramome, which allows one to study the early transcriptional responses to the Yamanaka factors in the perspective of reprogramming legitimacy of a gene response to reprogramming. Using RNA-seq, this study scored 579 genes successfully reprogrammed within 48 hours, indicating the potency of the reprogramming factors. This report also tallied 438 genes reprogrammed significantly but insufficiently up to 72 hours, indicating a positive drive with some inadequacy of the Yamanaka factors. In addition, 953 member genes within the reprogramome were transcriptionally irresponsive to reprogramming, showing the inability of the reprogramming factors to directly act on these genes. Furthermore, there were 305 genes undergoing six types of aberrant reprogramming: over, wrong, and unwanted up- or down- reprogramming, revealing significant negative impacts of the Yamanaka factors. The mixed findings about the initial transcriptional responses to the reprogramming factors shed new insights into the robustness as well as limitations of the Yamanaka factors.
2020-06-07 | GSE148158 | GEO
Project description:Human iPS cells were differentiated to cholangiocyte-like cells thorugh five phases of endodermal differentiation. Human iPSC were generated by forced expression of the Yamanaka pluripotency factors. We then pursued a stepwise differentiation strategy toward iDCs, using precise temporal exposure to key biliary morphogens, and we characterized the cells, using a variety of morphologic, molecular, cell biologic, functional, and in vivo approaches.
2016-08-25 | E-GEOD-86007 | biostudies-arrayexpress
Project description:Hutchinson Gilford Progeria Syndrome (HGPS) is a rare, sporadic genetic disease caused by mutations in the nuclear lamin A gene. In most cases the mutation creates an efficient donor-splice site that generates an altered transcript encoding a truncated lamin A protein, progerin. In vitro studies have indicated that progerin can disrupt nuclear function. HGPS affects mainly mesenchymal lineages but the shortage of patient material has precluded a tissue-wide molecular survey of progerin’s cellular impact. We report here a new, induced pluripotent stem cell (iPSC)-based model for studying HGPS. HGPS dermal fibroblasts were reprogrammed into iPSC lines using a cocktail of the transcription factor genes, OCT4, SOX2, KLF4 and C-MYC. The iPSC cells were differentiated into neural progenitors (NPs), endothelial cells (ECs), fibroblast-like cells and mesenchymal stem cells (MSCs). Progerin levels in the different cell types followed the pattern MSC≥ fibroblast>EC>>NP. Functionally, we detected a major impact of progerin on MSC function. We show that HGPS-MSCs are vulnerable to the ischemic conditions found in a murine hind limb recovery model and an in vitro hypoxia assay, as well as showing enhanced sensitivity in a serum starvation assay. Since there is widespread consensus that MSCs reside in low oxygen niches in vivo, we propose that these conditions lead to an accelerated depletion of the MSC pool in HGPS patients with consequent accretion of mesenchymal tissue. Analysis of iPSCs, hESCs and parental fibroblasts at the gene expression level. The comparison analysis in the present study was expected to show the similarity between iPSCs, hESCs and parental fibroblasts. Results provide important information of the differences between iPSCs, hESCs and parental fibroblasts. Total RNA was obtained from different samples (iPSCs, hESCs, and fibroblasts) separately.
2010-12-23 | E-GEOD-26093 | biostudies-arrayexpress
Project description:We generated three kinds of genetically identical mouse reprogrammed cells: induced pluripotent stem cells (iPSCs), nuclear transfer embryonic stem cells (ntESCs) and iPSC-nt-ESCs that are established after successively reprogramming of iPSCs by nuclear transfer (NT). NtESCs show better developmental potential than iPSCs, whereas iPSC-nt-ESCs display worse developmental potential than iPSCs. We used microarrays to distinguish the gene expression differences among three pluriptoent stem cells and identified that imprinted genes had a similar expression pattern in iPSCs and iPSC-nt-ESCs. We sought to obtain genetic identical pluripotent stem cell lines in order to minimize genetic variations among different reprogrammed cells. To that end, we established a genetically homogenous secondary reprogramming system, in which mouse embryonic fibroblasts (MEFs) carrying doxycycline (dox)-inducible lentiviruses expressing Oct4, Sox2, Klf4 and c-Myc were isolated and used as donors for different reprogramming experiments. We generated iPSCs after plating MEFs in the presence of dox in ES culture conditions, and then derived ntESCs after transplantation of the nucleus from the same MEFs into enucleated oocyte. Furthermore, we successively reprogrammed iPSCs by means of NT and established a set of nt-iPSC lines. Pluripotent stem cells generated from different reprogramming strategies were for RNA extraction and hybridization on Affymetrix microarrays.
2011-05-31 | E-GEOD-24705 | biostudies-arrayexpress
Project description:We generated three kinds of genetically identical mouse reprogrammed cells: induced pluripotent stem cells (iPSCs), nuclear transfer embryonic stem cells (ntESCs) and iPSC-nt-ESCs that are established after successively reprogramming of iPSCs by nuclear transfer (NT). NtESCs show better developmental potential than iPSCs, whereas iPSC-nt-ESCs display worse developmental potential than iPSCs. We used microarrays to distinguish the gene expression differences among three pluriptoent stem cells and identified that imprinted genes had a similar expression pattern in iPSCs and iPSC-nt-ESCs.
2011-05-31 | GSE24705 | GEO