scholarly journals Early divergence of mutational processes in human fetal tissues

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw1271 ◽  
Author(s):  
Ewart Kuijk ◽  
Francis Blokzijl ◽  
Myrthe Jager ◽  
Nicolle Besselink ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adult Stem Cells ◽  
Fetal Liver ◽  
Mutation Accumulation ◽  
Intestinal Stem Cells ◽  
Adult Liver ◽  
Fetal Tissues ◽  
Genetic Mosaicism ◽  
Human Fetal Tissues ◽  
Mutational Processes

A developing human fetus needs to balance rapid cellular expansion with maintaining genomic stability. Here, we accurately quantified and characterized somatic mutation accumulation in fetal tissues by analyzing individual stem cells from human fetal liver and intestine. Fetal mutation rates were about fivefold higher than in tissue-matched adult stem cells. The mutational landscape of fetal intestinal stem cells resembled that of adult intestinal stem cells, while the mutation spectrum of fetal liver stem cells is distinct from stem cells of the fetal intestine and the adult liver. Our analyses indicate that variation in mutational mechanisms, including oxidative stress and spontaneous deamination of methylated cytosines, contributes to the observed divergence in mutation accumulation patterns and drives genetic mosaicism in humans.

scholarly journals Early divergence of mutational mechanisms drives genetic heterogeneity of fetal tissues

2018 ◽  
Author(s):  
Ewart Kuijk ◽  
Francis Blokzijl ◽  
Myrthe Jager ◽  
Nicolle Besselink ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adult Stem Cells ◽  
Fetal Liver ◽  
Mutation Accumulation ◽  
Intestinal Stem Cells ◽  
Fetal Tissues ◽  
Dna Mutations ◽  
Genetic Mosaicism ◽  
Human Fetal Development ◽  
Early Human

AbstractA developing human fetus needs to balance rapid cellular expansion with maintaining genomic stability. Here, we accurately quantified and characterized somatic mutation accumulation in fetal tissues by analyzing individual stem cells from human fetal liver and intestine. Fetal mutation rates were ~5-fold higher than in tissue-matched adult stem cells. The mutational landscape of fetal intestinal stem cells resembled that of adult intestinal stem cells, while the mutation spectrum of fetal liver stem cells is distinct from stem cells of the fetal intestine and the adult liver. Our analyses indicate that variation in mutational mechanisms, including oxidative stress and spontaneous deamination of methylated cytosines, contribute to the observed divergence in mutation accumulation patterns and drive genetic mosaicism in humans.One Sentence SummaryLiver and intestinal cells accumulate elevated amounts and diverged types of somatic DNA mutations during early human fetal development

scholarly journals Human Fetal Liver: AnIn VitroModel of Erythropoiesis

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Guillaume Pourcher ◽  
Christelle Mazurier ◽  
Yé Yong King ◽  
Marie-Catherine Giarratana ◽  
Ladan Kobari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Large Scale ◽  
Adult Stem Cells ◽  
Fetal Liver ◽  
Es Cells ◽  
Embryonic Stem ◽  
Scale Production ◽  
Cloning Efficiency ◽  
Hematopoietic Stem

We previously described the large-scale production of RBCs from hematopoietic stem cells (HSCs) of diverse sources. Our present efforts are focused to produce RBCs thanks to an unlimited source of stem cells. Human embryonic stem (ES) cells or induced pluripotent stem cell (iPS) are the natural candidates. Even if the proof of RBCs production from these sources has been done, their amplification ability is to date not sufficient for a transfusion application. In this work, our protocol of RBC production was applied to HSC isolated from fetal liver (FL) as an intermediate source between embryonic and adult stem cells. We studied the erythroid potential of FL-derived CD34+cells. In thisin vitromodel, maturation that is enucleation reaches a lower level compared to adult sources as observed for embryonic or iP, but, interestingly, they (i) displayed a dramaticin vitroexpansion (100-fold more when compared to CB CD34+) and (ii) 100% cloning efficiency in hematopoietic progenitor assays after 3 days of erythroid induction, as compared to 10–15% cloning efficiency for adult CD34+cells. This work supports the idea that FL remains a model of study and is not a candidate forex vivoRBCS production for blood transfusion as a direct source of stem cells but could be helpful to understand and enhance proliferation abilities for primitive cells such as ES cells or iPS.

scholarly journals Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues.

1988 ◽  
Vol 168 (3) ◽  
pp. 1061-1080 ◽  
Author(s):  
B F Haynes ◽  
M E Martin ◽  
H H Kay ◽  
J Kurtzberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Phenotypic Characterization ◽  
Hematopoietic Stem ◽  
Fetal Tissues ◽  
Human T Cell ◽  
Human Fetal Tissues ◽  
Early Human

During early fetal development, T cell precursors home from fetal yolk sac and liver to the epithelial thymic rudiment. From cells that initially colonize the thymus arise mature T cells that populate T cell zones of the peripheral lymphoid system. Whereas colonization of the thymus occurs late in the final third of gestation in the mouse, in birds and humans the thymus is colonized by hematopoietic stem cell precursors during the first third of gestation. Using a large series of early human fetal tissues and a panel of monoclonal antibodies that includes markers of early T cells (CD7, CD45), we have studied the immunohistologic location and differentiation capacity of CD45+, CD7+ cells in human fetal tissues. We found that before T cell precursor colonization of the thymus (7-8 wk of gestation), CD7+ cells were present in yolk sac, neck, upper thorax, and fetal liver, and were concentrated in mesenchyme throughout the upper thorax and neck areas. By 9.5 wk of gestation, CD7+ cells were no longer present in upper thorax mesenchyme but rather were localized in the lymphoid thymus and scattered throughout fetal liver. CD7+, CD2-, CD3-, CD8-, CD4-, WT31- cells in thorax and fetal liver, when stimulated for 10-15 d with T cell-conditioned media and rIL-2, expressed CD2, CD3, CD4, CD8, and WT31 markers of the T cell lineage. Moreover, CD7+ cells isolated from fetal liver contained all cells in this tissue capable of forming CFU-T colonies in vitro. These data demonstrate that T cell precursors in early human fetal tissues can be identified using a mAb against the CD7 antigen. Moreover, the localization of CD7+ T cell precursors to fetal upper thorax and neck areas at 7-8.5 wk of fetal gestation provides strong evidence for a developmentally regulated period in man in which T cell precursors migrate to the epithelial thymic rudiment.

scholarly journals Identification of a new allele of O-fucosyltransferase 1 involved in Drosophila intestinal stem cell regulation

Biology Open ◽  
2021 ◽  
Vol 10 (11) ◽  
Author(s):  
Lin Shi ◽  
Ruiyan Kong ◽  
Zhengran Li ◽  
Hang Zhao ◽  
Rui Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adult Stem Cells ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
P Element ◽  
Intestinal Stem Cells ◽  
Genetic Screens ◽  
Stem Cell Regulation ◽  
Proliferation And Differentiation ◽  
Forward Genetic Screens

ABSTRACT Adult stem cells are critical for the maintenance of tissue homeostasis. However, how the proliferation and differentiation of intestinal stem cells (ISCs) are regulated remains not fully understood. Here, we find a mutant, stum 9-3, affecting the proliferation and differentiation of Drosophila adult ISCs in a forward genetic screen for factors regulating the proliferation and differentiation ISCs. stum 9-3 acts through the conserved Notch signaling pathway, upstream of the S2 cleavage of the Notch receptor. Interestingly, the phenotype of stum 9-3 mutant is not caused by disruption of stumble (stum), where the p-element is inserted. Detailed mapping, rescue experiments and mutant characterization show that stum 9-3 is a new allele of O-fucosyltransferase 1 (O-fut1). Our results indicate that unexpected mutants with interesting phenotype could be recovered in forward genetic screens using known p-element insertion stocks.

THE EFFECTS OF ANOXIA ON THE METABOLISM OF HUMAN FETAL TISSUES

PEDIATRICS ◽  
1958 ◽  
Vol 22 (5) ◽  
pp. 953-971 ◽  
Author(s):  
Claude A. Villee ◽  
Dwain D. Hagerman ◽  
Nils Holmberg ◽  
John Lind ◽  
Dorothy B. Villee
Keyword(s):  
Cerebral Cortex ◽  
Fetal Liver ◽  
Krebs Cycle ◽  
Enzymatic Reactions ◽  
Anaerobic Conditions ◽  
Tissue Slices ◽  
Aerobic Conditions ◽  
Fetal Tissues ◽  
Human Fetal Tissues

The problem of any organism surviving under anaerobic conditions is to convert the potential energy of its substrate molecules into biologically useful energy without having to use molecular oxygen. The resistance of the fetal and newborn mammal to hypoxia might depend upon some unique chemical reaction, upon quantitative differences in the rates of certain enzymatic reactions common to fetal and adult tissues, or upon a lower rate of cellular metabolism in fetal tissues. These experiments with human fetal tissues favor the second of these three possibilities. Tissue slices of human liver, cerebral cortex, brain stem, heart, lung, kidney and skeletal muscle were incubated in a medium containing C14 labeled glucose, fructose, pyruvic acid or acetic acid. These experiments showed that there is a fourfold greater rate of glycolysis in fetal liver midway through gestation under anaerobic conditions than under aerobic conditions. In contrast, the rate of lipogenesis under anaerobic conditions was only one-tenth as great as the rate under aerobic conditions. Experiments revealed that after a slice of liver or cerebral cortex had spent a full hour in complete anoxia, its ability to synthesize fatty acids and to oxidize substances by way of the Krebs cycle was essentially unimpaired. All of the experiments were designed to test the maximal activity of the enzyme systems involved. An excess of substrate was provided so that the activity of the cellular enzymes, and not the concentration of the substrate, was the ratelimiting factor. These experiments provide an estimate of the upper limit of the metabolic activity of the tissue in oxygen and in nitrogen. They do not provide an estimate of metabolic rates in vivo. Observations on human tissues near term showed that the rate of aerobic lipogenesis was much less than that observed in tissues of younger fetuses. This was equally true with labeled glucose, pyruvate and acetate as substrates. The pattern of lipogenesis is comparable to that in the liver of a rat 24 hours after parturition and not to the pattern which obtains in the rat just before birth. The rate of anaerobic lipogenesis is substantially less than that under aerobic conditions. These observations may be correlated with the idea that the newborn rat is more immature than the newborn human. These experiments indicate that lipogenesis is of no significance in the ability of the human fetus one half way through gestation to withstand hypoxia, for under anaerobic conditions lipogenesis is decreased whereas glycolysis is increased.

scholarly journals Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging

2015 ◽  
Vol 17 (6) ◽  
pp. 663-674 ◽  
Author(s):  
Katarzyna Siudeja ◽  
Sonya Nassari ◽  
Louis Gervais ◽  
Patricia Skorski ◽  
Sonia Lameiras ◽  
...  
Keyword(s):  
Stem Cells ◽  
Somatic Mutation ◽  
Intestinal Stem Cells ◽  
Genetic Mosaicism

Measuring mutation accumulation in single human adult stem cells by whole-genome sequencing of organoid cultures

2017 ◽  
Vol 13 (1) ◽  
pp. 59-78 ◽  
Author(s):  
Myrthe Jager ◽  
Francis Blokzijl ◽  
Valentina Sasselli ◽  
Sander Boymans ◽  
Roel Janssen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Adult Stem Cells ◽  
Mutation Accumulation ◽  
Whole Genome ◽  
Human Adult ◽  
Organoid Cultures
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