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 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 “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk

Dose-Response ◽  
2017 ◽  
Vol 15 (2) ◽  
pp. 155932581771658 ◽  
Author(s):  
James E. Trosko ◽  
Giuseppe Carruba
Keyword(s):  
Stem Cells ◽  
Dna Repair ◽  
Dna Replication ◽  
Adult Stem Cells ◽  
Extended Period ◽  
Developmental State ◽  
Extrinsic Factors ◽  
Dna Mutations ◽  
Organ Specific ◽  
In Utero Development

It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with mutations found in cancers associated with these exposures. While support for both interpretations provides some validity, both interpretations ignore several concepts of the multistage, multimechanism process of carcinogenesis, namely, (1) mutations can be generated by both “errors of DNA repair” and “errors of DNA replication,” during the “initiation” process of carcinogenesis; (2) “initiated” stem cells must be clonally amplified by nonmutagenic, intrinsic or extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be modified during in utero development, thereby altering the risk to cancer later in life; and (4) epigenetic tumor promoters are characterized by species, individual genetic-, gender-, developmental state-specificities, and threshold levels to be active; sustained and long-term exposures; and exposures in the absence of antioxidant “antipromoters.” Because of the inevitability of some of the stem cells generating “initiating” mutations by either “errors of DNA repair” or “errors of DNA replication,” a tumor is formed depending on the promotion phase of carcinogenesis. While it is possible to reduce our frequencies of mutagenic “initiated” cells, one can never reduce it to zero. Because of the extended period of the promotion phase of carcinogenesis, strategies to reduce the appearance of cancers must involve the interruption of the promotion of these initiated cells.

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.

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

scholarly journals MLL1 is required for maintenance of intestinal stem cells and the expression of the cell adhesion molecule JAML

2020 ◽  
Author(s):  
Neha Goveas ◽  
Claudia Waskow ◽  
Kathrin Arndt ◽  
Julian Heuberger ◽  
Qinyu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adhesion Molecule ◽  
Adult Stem Cells ◽  
Paneth Cells ◽  
Intestinal Stem Cells ◽  
Epigenetic Mark ◽  
Hematopoietic Stem ◽  
Histone 3 ◽  
H3k4 Methyltransferases

AbstractEpigenetic control is crucial for lineage-specific gene expression that creates cellular identity during mammalian development and in adult organism. Histone 3 lysine 4 methylation (H3K4) is a universal epigenetic mark. Mixed lineage leukemia (MLL1) is the founding member of the mammalian family of H3K4 methyltransferases. It was originally discovered as the main gene mutated in early onset leukemias and then found to be required for hematopoietic stem cell development and maintenance. However, the roles of MLL1 in non-hematopoietic tissues remain largely unexplored. To bypass hematopoietic lethality, we used bone marrow transplantation and conditional mutagenesis to discover that the most overt phenotype in Mll1-mutant mice is intestinal failure. Loss of MLL1 is accompanied by a differentiation bias towards the secretory lineage with increased numbers of goblet cells. MLL1 is expressed in intestinal stem cells (ISCs) and transit amplifying (TA) cells but at reduced levels in Paneth cells and not in the villus. MLL1 is required for the maintenance of intestinal stem cells (ISCs) and proliferation in the crypt. Transcriptome analysis implicate MLL1-dependent expression in ISCs of several transcription factors including Pitx2, Gata4, Foxa1 and Onecut2, and also a cell adhesion molecule, Jaml. Reactive transcriptome changes in Paneth cells and organoids imply that JAML plays a key role in the crypt stem cell niche. All known postnatal functions of MLL1 relate to stem cell maintenance and lineage decisions thereby highlighting the suggestion that MLL1 is a master stem cell regulator.Author SummaryThe ability of adult stem cells to produce functional progenies through differentiation is critical to maintain function and integrity of organs. A fundamental challenge is to identify factors that control the transition from self-renewal to the differentiated state. Epigenetic factors amongst others can fullfill such a role. Methylation of histone 3 on lysine 4 (H3K4) is a posttranslational epigenetic modification that is associated with actively transcribed genes. In mammals, this epigenetic mark is catalyzed by one of six H3K4 methyltransferases, including the founding member of the family, MLL1. MLL1 is important for the precise functioning of the hematopoietic stem cell compartment. This raises the possibility of similar functions in other adult stem cell compartments. Due to its intense self-renewal kinetics and its simple repetitive architecture, the intestinal epithelium serves as a prime model for studying adult stem cells. We demonstrate that MLL1 controls intestinal stem cell proliferation and differentiation. Additionally, transcriptome analysis suggests a pertubation in the close interaction between intestinal stem cells and neighbouring Paneth cells through loss of junction adhesion molecule like (JAML). Our work sheds new light on the function of MLL1 for the control of intestinal stem cell identity.

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