This SuperSeries is composed of the SubSeries listed below.
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Specimen part
View SamplesWhile disease recurrence remains the outstanding clinical challenge in acute myeloid leukemia (AML), the basis of relapse remains poorly characterized and thereby preventing effective therapeutic targeting. We performed gene expression analysis of human AML patient samples in addition to in vitro and in vivo assays of leukemic cell survival and self-renewal using xenograft modeling. These molecular and functional analyses afforded the identification of unique target genes that support recurrence. Preclinical modeling using these novel targets provided proof-of-principle for combination therapies towards more effective and durable suppression of AML regrowth.
Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence.
Specimen part
View SamplesCell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. To describe these changes, investigators have relied extensively on the study of immortalized rodent cell lines or heterogeneous tumor samples that limit the identification of differentially expressed genes or may not represent the full spectrum of biological processes regulated during transformation. In this study, we took advantage of transformation-deficient and temperature sensitive mutants of the Rous sarcoma virus to characterize the patterns of gene expression in two types of primary cells, namely chicken embryo fibroblasts (CEF) and chicken neuro-retinal (CNR) cells.
Cellular processes of v-Src transformation revealed by gene profiling of primary cells--implications for human cancer.
No sample metadata fields
View SamplesHuman 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.
Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states.
Specimen part
View SamplesTo investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEF expressing either the c-Jun dominant-negative mutant TAM67 or JunD shRNA.
JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.
Specimen part
View SamplesHuman 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.
Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
Specimen part
View SamplesGene expression was examined in testis and brain tissue between two species (Xenopus laevis and Xenopus borealis) and their hybrid.
Single-species microarrays and comparative transcriptomics.
Age
View SamplesHuman pluripotent stem cells (hPSC) generate hematopoietic progenitor cells (HPC), but fail to engraft xenograft models, which is a hallmark feature of adult/somatic hematopoietic stem cells (HSC) from human donors. Progress to derive hPSC-derived HSCs has relied on cell autonomous approaches that force expression of transcription factors (TF), however the role of bone marrow (BM) niche remains poorly understood. Here, we quantified a failure of hPSC-HPCs to survive even in the first 24 h upon transplantation into the BM. Across several hPSC-HPC differentiation methodologies, we identified the lack of CXCR4 expression and network function. Ectopic CXCR4 conferred CXCL12-dependent signaling of hPSC-HPCs in biochemical assays and increased migration/chemotaxis and progenitor capacity, as well as survival and proliferation following transplantation in vivo. In addition, hPSC-HPCs forced to express CXCR4 demonstrated a transcriptional shift toward somatic HPCs, but this approach failed to produce long-term HSC engraftment. Our results reveal that independent of differentiation methods, networks involving CXCR4 should be targeted to generate HSCs with in vivo function from hPSCs.
CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor Function and Overcomes Early In Vivo Transplantation Failure.
Specimen part
View SamplesHematopoietic progenitors from AML patients express the aryl hydrocarbon receptor signaling pathway. Independent of in vivo engraftability to detect leukemic stem cells, AHR antagonism allows in vitro survival and expansion of AML progenitors, while retaining patient-to-patient heterogeneity.
No associated publication
Specimen part
View SamplesTo investigate the differences of expression patterns in primary chicken embryo fibroblasts (CEFs) under conditions of contact-inhibition and serum starvation, we undertook a gene profiling study to characterize the transcriptomes of CEFs grown under conditions of contact inhibition, serum starvation or both, in relation to normal growing (cycling) cells.
Extracellular Signal-Regulated Kinase 2 and CHOP Restrict the Expression of the Growth Arrest-Specific p20K Lipocalin Gene to G0.
Specimen part
View Samples