Topic
Cellular differentiation
About: Cellular differentiation is a research topic. Over the lifetime, 90966 publications have been published within this topic receiving 6099252 citations. The topic is also known as: Cellular differentiation & GO:0030154.
Papers published on a yearly basis
Papers
More filters
TL;DR: Different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively.
731 citations
TL;DR: The data argue for a model in which IFN-γ gene regulation involves an autocrine loop, whereby the cytokine regulates a transcription factor that promotes its own production, and substantially alter the current view of T-bet in IFn-γ regulation and promotion of cell-mediated immune responses.
Abstract: Differentiation of naive CD4(+) T cells into IFN-gamma-producing T helper 1 (T(H)1) cells is pivotal for protective immune responses against intracellular pathogens. T-bet, a recently discovered member of the T-box transcription factor family, has been reported to play a critical role in this process, promoting IFN-gamma production. Although terminal T(H)1 differentiation occurs over days, we now show that challenge of mice with a prototypical T(H)1-inducing stimulus, Toxoplasma gondii soluble extract, rapidly induced IFN-gamma and T-bet; T-bet induction was substantially lower in IFN-gamma-deficient mice. Naive T cells expressed little T-bet, but this transcription factor was induced markedly by the combination of IFN-gamma and cognate antigen. Human myeloid antigen-presenting cells showed T-bet induction after IFN-gamma stimulation alone, and this induction was antagonized by IL-4 and granulocyte/macrophage colony-stimulating factor. Although T-bet was induced rapidly and directly by IFN-gamma, it was not induced by IFN-alpha, lipopolysaccharide, or IL-1, indicating that this action of IFN-gamma was specific. Moreover, T-bet induction was dependent on Stat1 but not Stat4. These data argue for a model in which IFN-gamma gene regulation involves an autocrine loop, whereby the cytokine regulates a transcription factor that promotes its own production. These findings substantially alter the current view of T-bet in IFN-gamma regulation and promotion of cell-mediated immune responses.
730 citations
TL;DR: It is revealed that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
Abstract: The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
730 citations
TL;DR: The results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus and suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.
Abstract: Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.
729 citations
TL;DR: The de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells is reported, describing a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease.
Abstract: Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world's population and are largely due to chronic Helicobacter pylori infection Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis, and there is no experimental model of normal human gastric mucosa Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs) Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells We used hGO cultures to identify novel signalling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3 Using hGOs to model pathogenesis of human disease, we found that H pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signalling and induction of epithelial proliferation Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease
729 citations