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Homo sapiens
8 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Similar to embryo-derived stem cells, application of human induced pluripotent stem cells (iPSCs) is limited by our understanding of lineage specification. Here, we demonstrate the ability to generate progenitors and mature cells of the hematopoietic fate directly from human dermal fibroblasts without establishing pluripotency. POU domain activation of hematopoietic transcription factors by ectopic expression of Oct-4, together with specific cytokine treatment, allowed generation of cells expressing the pan-leukocyte marker CD45. These unique fibroblast-derived cells gave rise to granulocytic, monocytic, megakaryocytic, and
Publication Title
Direct conversion of human fibroblasts to multilineage blood progenitors.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Human induced pluripotent stem cells (hiPSCs) provide an invaluable source for regenerative medicine; but are limited by proficient lineage specific differentiation. Here we reveal that hiPSCs derived from dermal skin fibroblasts (Fib) vs. human cord blood (CB) cells exhibit equivalent and indistinguishable pluripotent properties, but harbor important propensities for neural and hematopoietic lineage differentiation, independent of reprogramming factors used. Genes associated with germ layer specification were identical in both Fib or CB derived iPSCs; whereas patterns of lineage specific marks emerge upon differentiation induction of hiPSCs that were correlated to the cell type of origin used to create hiPSCs. Functionally, CB-iPSCs predominantly differentiate into hematopoietic cells and even adopt definitive hematopoiesis as evidenced by adult -globin positive red blood cell development whereas Fib-iPSCs possess enhanced neural capacity. These clear differentiation propensities come at the expense of other lineages and cannot be overcome with additional external stimuli for alternative cell fates. Moreover, these differences in developmental potential are encoded within cultures of CB vs. Fib derived hiPSCs that can be used to predict differentiation propensity.
Publication Title
Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 83 Downloadable Samples
Illumina HiSeq 1500
Description
Human pluripotent stem cells (hPSCs) have been reported in naïve and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the naïve state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in naïve hPSCs and thus failed to predict biased functional differentiation. Naïve hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore naïve hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient naïve hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications. Overall design: hPSC lines were transduced with shRNA lentiviruses in order to assess the effects of reducing NANOG and OCT4 gene expression on differention in the naïve state. shRNA expressing cells were sorted and then total RNA was extracted in order to perform transcriptome profiling by RNA-seq. Each experimental condition involves 2 technical replicates of 2 biological replicates (2 tech X 2 biol = 4 reads).
Publication Title
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus, Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Human pluripotent stem cells (hPSCs) have been reported in nave and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the nave state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in nave hPSCs and thus failed to predict biased functional differentiation. Nave hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore nave hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient nave hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
Publication Title
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Human pluripotent stem cells (hPSCs) have been reported in nave and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the nave state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in nave hPSCs and thus failed to predict biased functional differentiation. Nave hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore nave hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient nave hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
Publication Title
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Direct cell fate conversion allows the generation of somatic cells that are otherwise difficult to obtain directly from patients. The clinical applicability of this approach depends on obtaining an initial source of somatic cells from adult patients that is easy to harvest, store, and manipulate for reprogramming. Here we have generated induced neural progenitor cells (iNPCs) from neonatal as well as peripheral blood from human adults using single factor OCT4 based reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, direct OCT4 reprogramming of human blood could be facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood derived (BD)-iNPCs functionally differentiate in vivo, and respond to guided differentiation in vitro to produce both glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes including dopamine releasing DA neurons (CNS related) and nociceptive neurons (PNS). Furthermore, BD nociceptive neurons phenocopy chemotherapy induced neurotoxicity in a system suitable for high throughput drug screening. Our findings provide an easily accessible approach to generate human NPCs that harbor extensive developmental potential, enabling the study of clinically relevant neural diseases directly from patient cohorts.
Publication Title
Single Transcription Factor Conversion of Human Blood Fate to NPCs with CNS and PNS Developmental Capacity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The cellular origin and molecular progression towards aggressive cancers such as acute myeloid leukemia (AML) remain elusive. Clinically, Myelodysplastic syndromes (MDS) and related myeloproliferative neoplasias (MPN) disorders1-5 are believed to present as a precursor stage to lethal AML development. Despite the identification of cytogenetic abnormalities and increased activation of signaling in human MDS/MPN, specific pathways that either sustain or initiate disease progression and evolve into self-sustaining leukemic-initiating cells (L-ICs)13 have not been elucidated. Here we demonstrate that tissue specific loss of glycogen synthase kinase-3 (GSK3 beta) initiates the emergence of stable Pre-leukemic-ICs (PLIC) in vivo. In contrast to deletion or transgenic perturbation of pathways associated with AML eg. -catenin/Wnt, serial transplantation of PL-IC produced abnormal hematological disease that phenotypically and molecularly resembles human MDS/MPN. PL-ICs were exclusively generated from GSK3 beta deficient hematopoietic stem cells (HSCs), indicating that disease initiation events collaborate with existing HSC self-renewal machinery. In the absence of GSK3 beta, subsequent deletion of GSK3 beta caused rapid induction of L-ICs that give rise to lethal AML. As these processes were solely driven by dose-dependent deficiencies in GSK3 beta levels, our results suggest that perturbation of this pathway can sufficiently drive and recapitulate a step-wise progression of disease from HSCs to MDS/MPN and subsequent AML. Our study provides a molecular and cellular foundation to understand AML evolution from pre-leukemic precursors. We suggest that defining the molecular states of pre-neoplastic disease will allow patient stratification at early stages of MDS/MPN onset and aid in the development of therapeutic targeting of causal pathways responsible for the earliest stages of leukemic initiation events.
Publication Title
GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures. Methods: We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of different potential stem cell markers: CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts mRNA expression of the investigated markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo. Results: All surface markers showed distinct expression patterns in the examined tumours. Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated markers. CD44 and CXCR4 mRNA expression correlated within the cell line panel and CD44 and CDCP1 within the xenograft panel, respectively. Small subpopulations of double and triple positive cells could be described. SW620 showed significantly higher take rates and shorter doubling times in vivo when sorted for CD133 positivity. Conclusion: Our data support the hypothesis of a small subset of cells with stem cell-like properties characterized by a distinct surface marker profile. In vivo growth kinetics give strong relevance for an important role of CD133 within the mentioned surface marker profile.
Publication Title
Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples
GSE1557- Rattus norvegicus
- 4 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a)
Description
Rats overexpressing the human renin and angiotensinogen genes die after seven weeks of end organ damage. They develop hypertension, heart hypertrophy and proteinuria.We compared terminal heart failure, these are indeed terminally ill to double transgenic animals suffering on hypertension, proteinuria and heart hypertrophy. In addition, Losartan-treated animals (10 mg/kg/d)showed similar physiological parameters (normotension, no proteinuria and no heart hypertrophy compared to control sprague dawley rats.
Publication Title
Cardiac gene expression profile in rats with terminal heart failure and cachexia.
Sample Metadata Fields
No sample metadata fields
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