scholarly journals Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

2018 ◽  
Author(s):  
Karina Vázquez-Arreguín ◽  
Claire Bensard ◽  
John C. Schell ◽  
Eric Swanson ◽  
Xinjian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Colon Cancer ◽  
Transcription Factor ◽  
Stem Cell ◽  
The United States ◽  
Mitotic Stability ◽  
Cell Compartments ◽  
Incidence And Mortality ◽  
Gene Expression Signatures

AbstractThe transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to generate cultured organoids in vitro, but blocked the ability to regenerate after treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or bothOct1alleles progressively increased tumor burden in a colon cancer model driven by loss of heterozygosity of the tumor suppressor geneApc.The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with different gene expression signatures associated with the two models. These results reveal that Oct1 is selectively required for gut regeneration, and has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology.Author summaryColorectal cancer is the second leading cause of cancer death in the United States. Approximately 35% of diagnosed patients eventually succumb to disease. The high incidence and mortality due to colon cancer demand a better understanding of factors controlling the physiology and pathophysiology of the gastrointestinal tract. Previously, we and others showed that the widely expressed transcription factor is expressed at higher protein levels in stem cells, including intestinal stem cells. In this study we use a conditional mouseOct1(Pou2f1) allele deleted in two different intestinal stem cell compartments. The results indicate that Oct1 loss is dispensable for maintenance of the mouse gut, but required for regeneration. We also tested Oct1 loss in the context of two different mouse colon cancer models. We find that Oct1 loss has opposing effects in the two models, and further that the two models are associated with different gene expression signatures. The differentially expressed genes are enriched for previously identified Oct1 targets, suggesting that differential gene control by Oct1 is one mechanism underlying different outcomes.

scholarly journals MicroRNA treatment modulates osteogenic differentiation potential of mesenchymal stem cells derived from human chorion and placenta

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kulisara Marupanthorn ◽  
Chairat Tantrawatpan ◽  
Pakpoom Kheolamai ◽  
Duangrat Tantikanlayaporn ◽  
Sirikul Manochantr
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Osteogenic Gene Expression ◽  
Osteogenic Gene

AbstractMesenchymal stem cells (MSCs) are important in regenerative medicine because of their potential for multi-differentiation. Bone marrow, chorion and placenta have all been suggested as potential sources for clinical application. However, the osteogenic differentiation potential of MSCs derived from chorion or placenta is not very efficient. Bone morphogenetic protein-2 (BMP-2) plays an important role in bone development. Its effect on osteogenic augmentation has been addressed in several studies. Recent studies have also shown a relationship between miRNAs and osteogenesis. We hypothesized that miRNAs targeted to Runt-related transcription factor 2 (Runx-2), a major transcription factor of osteogenesis, are responsible for regulating the differentiation of MSCs into osteoblasts. This study examines the effect of BMP-2 on the osteogenic differentiation of MSCs isolated from chorion and placenta in comparison to bone marrow-derived MSCs and investigates the role of miRNAs in the osteogenic differentiation of MSCs from these sources. MSCs were isolated from human bone marrow, chorion and placenta. The osteogenic differentiation potential after BMP-2 treatment was examined using ALP staining, ALP activity assay, and osteogenic gene expression. Candidate miRNAs were selected and their expression levels during osteoblastic differentiation were examined using real-time RT-PCR. The role of these miRNAs in osteogenesis was investigated by transfection with specific miRNA inhibitors. The level of osteogenic differentiation was monitored after anti-miRNA treatment. MSCs isolated from chorion and placenta exhibited self-renewal capacity and multi-lineage differentiation potential similar to MSCs isolated from bone marrow. BMP-2 treated MSCs showed higher ALP levels and osteogenic gene expression compared to untreated MSCs. All investigated miRNAs (miR-31, miR-106a and miR148) were consistently downregulated during the process of osteogenic differentiation. After treatment with miRNA inhibitors, ALP activity and osteogenic gene expression increased over the time of osteogenic differentiation. BMP-2 has a positive effect on osteogenic differentiation of chorion- and placenta-derived MSCs. The inhibition of specific miRNAs enhanced the osteogenic differentiation capacity of various MSCs in culture and this strategy might be used to promote bone regeneration. However, further in vivo experiments are required to assess the validity of this approach.

A microfluidic platform enables comprehensive gene expression profiling of mouse retinal stem cells

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Shana O Kelley ◽  
Mahmoud Labib ◽  
Brenda Coles ◽  
Mahla Poudineh ◽  
Brendan Innes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Visual Impairment ◽  
Gene Expression Profiling ◽  
Replacement Therapy ◽  
Retinal Degeneration ◽  
Expression Profiling ◽  
Cell Replacement Therapy ◽  
Cell Replacement

Loss of photoreceptors due to retinal degeneration is a major cause of untreatable visual impairment and blindness. Cell replacement therapy, using retinal stem cell (RSC)-derived photoreceptors, holds promise for reconstituting...

Positive regulators of the lineage-specific transcription factor GATA-1 in differentiating erythroid cells

1994 ◽  
Vol 14 (5) ◽  
pp. 3108-3114
Author(s):  
M H Baron ◽  
S M Farrington
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Cultured Cells ◽  
Globin Gene ◽  
Embryonic Stem ◽  
Targeted Mutagenesis ◽  
Erythroid Cell ◽  
Erythroid Cells

The zinc finger transcription factor GATA-1 is a major regulator of gene expression in erythroid, megakaryocyte, and mast cell lineages. GATA-1 binds to WGATAR consensus motifs in the regulatory regions of virtually all erythroid cell-specific genes. Analyses with cultured cells and cell-free systems have provided strong evidence that GATA-1 is involved in control of globin gene expression during erythroid differentiation. Targeted mutagenesis of the GATA-1 gene in embryonic stem cells has demonstrated its requirement in normal erythroid development. Efficient rescue of the defect requires an intact GATA element in the distal promoter, suggesting autoregulatory control of GATA-1 transcription. To examine whether GATA-1 expression involves additional regulatory factors or is maintained entirely by an autoregulatory loop, we have used a transient heterokaryon system to test the ability of erythroid factors to activate the GATA-1 gene in nonerythroid nuclei. We show here that proerythroblasts and mature erythroid cells contain a diffusible activity (TAG) capable of transcriptional activation of GATA-1 and that this activity decreases during the terminal differentiation of erythroid cells. Nuclei from GATA-1- mutant embryonic stem cells can still be reprogrammed to express their globin genes in erythroid heterokaryons, indicating that de novo induction of GATA-1 is not required for globin gene activation following cell fusion.

scholarly journals Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

2020 ◽  
Vol 31 (14) ◽  
pp. 1538-1549
Author(s):  
Fan Zhang ◽  
Mehdi Pirooznia ◽  
Hong Xu
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Stem Cell ◽  
Electron Transport Chain ◽  
Intestinal Stem Cell ◽  
Stem Cell Proliferation ◽  
Epithelial Homeostasis ◽  
Chain Complexes ◽  
Transport Chain

Deficiencies in electron transport chain complexes increase the activity of FOXO transcription factor in Drosophila midgut stem cells, which impairs stem cell proliferation and enterocyte specification.

scholarly journals Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

2020 ◽  
Author(s):  
Srivathsa S. Magadi ◽  
Chrysanthi Voutyraki ◽  
Gerasimos Anagnostopoulos ◽  
Evanthia Zacharioudaki ◽  
Ioanna K. Poutakidou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Transcription Factor ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Transcriptional Networks ◽  
Malignant Tumours ◽  
Stem Cell Maintenance

ABSTRACTNeural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

Abstract 300: Pathophysiologically Regulated Gene Expression in Human Stem & Progenitor Cells for Cardiogenic Differentiation and Repair

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Zhilin Chen ◽  
Sean R Hall ◽  
Keith R Brunt ◽  
Zhan Liu ◽  
David A Ademidun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Transgene Expression ◽  
Starting Point ◽  
Inflammatory Stimuli ◽  
Regulated Gene Expression ◽  
Cardiogenic Differentiation ◽  
Therapeutic Genes

Human stem and progenitor cells have emerged as potentially useful substrates for cardiovascular repair through neovascularization and myocardial regeneration. However, efficacy is limited by impedance to stem cell retention, homing and differentiation in hostile microenvironments, as occur in infarcted myocardium. The objective of the current study was to regulate gene function for tailored therapy in post infarct myocardium. Here we show that hypoxic and inflammatory stimuli of the infarct microenvironment regulate a proportional response in gene expression in human endothelial progenitor (EPC) and mesenchymal stem cells (MSC). Highly efficient lentiviral vectors incorporating hypoxia (HRE) and nuclear factor kappa B (NFkB) responsive elements are used to drive transgenes for survival, autologous stem cell homing and cardiogenic differentiation. Utilizing an internal cytomegalovirus promoter deleted lentiviral transfer vector, an HRE-NFkB bicistronic promoter-reporter vector was constructed with a modified internal ribosome entry sequence between green fluorescent protein and luciferase or therapeutic genes. Either hypoxia or inflammation resulted in a seven to ten-fold response of transgene expression assessed by luciferase activity in EPC (hypoxia, 7608±954; inflammation 11492±1384, P<0.01 and P<0.001 vs control 1049±139 respectively, N=6), while combined hypoxic-inflammatory stimuli resulted in a sixty-fold increase of transgene expression (hypoxic-inflammation, 62364±6609, P<0.001 vs control 1049±139, N=6). These results were recapitulated in MSC and with a series of therapeutic genes as determined by transcript, protein expression and activity. Our results demonstrate that regulated vectors provide a proportional response to hostile post-infarct myocardium. Translating cardiovascular regenerative medicine using stem cells requires managing stem cell survival, function and differentiation. Utilizing site-specific pathophysiological cues to auto-regulate reparative and regenerative gene expression, this study is a starting point for sophisticated platforms for patient tailored cell-based cardiogenic therapy.

Establishment of human OCT4 as a putative HSP90 client protein : a case for HSP90 chaperoning pluripotency

2015 ◽  
Author(s):  
◽  
Jason Neville Sterrenberg
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
Cell Biology ◽  
Therapeutic Potential ◽  
Stem Cell Biology ◽  
Client Protein ◽  
Hsp90 Inhibition ◽  
Regulated Gene Expression ◽  
Hsp90 Client Protein

The therapeutic potential of stem cells is already being harnessed in clinical trails. Of even greater therapeutic potential has been the discovery of mechanisms to reprogram differentiated cells into a pluripotent stem cell-like state known as induced pluripotent stem cells (iPSCs). Stem cell nature is governed and maintained by a hierarchy of transcription factors, the apex of which is OCT4. Although much research has elucidated the transcriptional regulation of OCT4, OCT4 regulated gene expression profiles and OCT4 transcriptional activation mechanisms in both stem cell biology and cellular reprogramming to iPSCs, the fundamental biochemistry surrounding the OCT4 transcription factor remains largely unknown. In order to analyze the biochemical relationship between HSP90 and human OCT4 we developed an exogenous active human OCT4 expression model with human OCT4 under transcriptional control of a constitutive promoter. We identified the direct interaction between HSP90 and human OCT4 despite the fact that the proteins predominantly display differential subcellular localizations. We show that HSP90 inhibition resulted in degradation of human OCT4 via the ubiquitin proteasome degradation pathway. As human OCT4 and HSP90 did not interact in the nucleus, we suggest that HSP90 functions in the cytoplasmic stabilization of human OCT4. Our analysis suggests HSP90 inhibition inhibits the transcriptional activity of human OCT4 dimers without affecting monomeric OCT4 activity. Additionally our data suggests that the HSP90 and human OCT4 complex is modulated by phosphorylation events either promoting or abrogating the interaction between HSP90 and human OCT4. Our data suggest that human OCT4 displays the characteristics describing HSP90 client proteins, therefore we identify human OCT4 as a putative HSP90 client protein. The regulation of the transcription factor OCT4 by HSP90 provides fundamental insights into the complex biochemistry of stem cell biology. This may also be suggestive that HSP90 not only regulates stem cell biology by maintaining routine cellular homeostasis but additionally through the direct regulation of pluripotency factors.

scholarly journals The The Influence of Mesenchymal Stem Cell Wharton Jelly toward Prostaglandin E2 Gene Expression on Synoviocyte Cell Osteoarthritis

2019 ◽  
Vol 7 (8) ◽  
pp. 1252-1258 ◽  
Author(s):  
Vivi Sofia ◽  
Moch Saiful Bachri ◽  
Rizki Rahmadian
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Prostaglandin E2 ◽  
Expression Analysis ◽  
Control Group ◽  
E2 Gene

BACKGROUND: Pharmacological therapy in the management of OA causes many new health problems due to side effects caused by long-term use of drugs, such as long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) will cause gastric ulcers and impaired kidney function. In OA pathogenesis, PGE2 gene is involved in the inflammation process. AIM: This study aims to identify the influence of Wharton Jelly Mesenchymal Stem Cell (MSC-WJ) on PGE2 expression gene in synoviocyte by in vitro. MATERIAL AND METHODS: The method used in this study is the co-culture method of primary cells and stem cells in the appropriate media. This research is pure experimental research. The sample used came from synovial tissue of osteoarthritis patients who underwent Total Knee Replacement (TKR) surgery. This study was divided into 6 groups treated with 4 replications. The expression analysis of the Prostaglandin E2 gene was done using qPCR (Real-Time Polymerase Chain Reaction). The expression analysis of the Prostaglandin E2 gene was carried out before and after the co-culture with Wharton's Jelly and continued with the analysis of statistical data processing using the SPSS.15 program. PGE2 gene expression data were processed using the Kruskal-Wallis test and continued with the Mann-Whitney test with a 95% confidence level. RESULTS: The results showed that Mesenchymal Stem Cells Wharton Jelly could reduce the expression of Prostaglandin E2 gene after co-culture for 24 hours and 48 hours in synoviocyte cells osteoarthritis significantly compared with the control group. The administration of Mesenchymal Stem Cells for 24 hours reduced the expression level of PGE2 gene by 0.61 times compared to the control group (p < 0.05) and the administration of Mesenchymal Stem Cells for 48 hours decreased the expression level of PGE2 gene by 0, 47 times compared to the control group (p < 0.05). CONCLUSION: This study concluded that MSC-WJ in OA synoviocyte significantly reduced the expression of the PGE2 gene (p < 0.05).

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