scholarly journals Highly rigid H3.1/H3.2–H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells

2022 ◽  
Author(s):  
Masashi Hada ◽  
Hisashi Miura ◽  
Akie Tanigawa ◽  
Shogo Matoba ◽  
Kimiko Inoue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Large Scale ◽  
Cell Types ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Genomic Reprogramming ◽  
Pluripotent Marker ◽  
High Degree

The placenta is a highly evolved, specialized organ in mammals. It differs from other organs in that it functions only for fetal maintenance during gestation. Therefore, there must be intrinsic mechanisms that guarantee its unique functions. To address this question, we comprehensively analyzed epigenomic features of mouse trophoblast stem cells (TSCs). Our genome-wide, high-throughput analyses revealed that the TSC genome contains large-scale (>1-Mb) rigid heterochromatin architectures with a high degree of histone H3.1/3.2–H3K9me3 accumulation, which we termed TSC-defined highly heterochromatinized domains (THDs). Importantly, depletion of THDs by knockdown of CAF1, an H3.1/3.2 chaperone, resulted in down-regulation of TSC markers, such as Cdx2 and Elf5, and up-regulation of the pluripotent marker Oct3/4, indicating that THDs maintain the trophoblastic nature of TSCs. Furthermore, our nuclear transfer technique revealed that THDs are highly resistant to genomic reprogramming. However, when H3K9me3 was removed, the TSC genome was fully reprogrammed, giving rise to the first TSC cloned offspring. Interestingly, THD-like domains are also present in mouse and human placental cells in vivo, but not in other cell types. Thus, THDs are genomic architectures uniquely developed in placental lineage cells, which serve to protect them from fate reprogramming to stably maintain placental function.

scholarly journals Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kylie Hin-Man Mak ◽  
Yuk Man Lam ◽  
Ray Kit Ng
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Cell Fate ◽  
Histone Demethylase ◽  
Gene Promoters ◽  
Transcriptional Program ◽  
Binding Motifs ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Trophoblast Stem Cell

AbstractTrophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

scholarly journals Derivation of macaque trophoblast stem cells

2020 ◽  
Author(s):  
Jenna Kropp Schmidt ◽  
Michael G. Meyer ◽  
Gregory J. Wiepz ◽  
Lindsey N. Block ◽  
Brittany M. Dusek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Culture Media ◽  
Syncytium Formation ◽  
First Trimester ◽  
Gonadotropin Secretion ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Mhc Class I Molecule

AbstractNonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSC) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first trimester placental villous cytotrophoblasts followed by culture in TSC medium to “reprogram” the cells to a proliferative state. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was >4,000-fold higher in ST culture media compared to TSC media. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and macaque placental nonclassical MHC class I molecule, Mamu-AG. TSC differentiation to extravillous trophoblasts (EVTs) with or without the ALK-5 inhibitor A83-01 resulted in differing morphologies but similar expression of Mamu-AG and CD56 as assessed by flow cytometry, hence further refinement of relevant EVT markers is needed. Our preliminary characterization of macaque TSCs suggests that these cells represent a proliferative, self-renewing TSC population capable of differentiating to STs in vitro thereby establishing an experimental model of primate placentation.

scholarly journals Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Bum-Kyu Lee ◽  
Yu jin Jang ◽  
Mijeong Kim ◽  
Lucy LeBlanc ◽  
Catherine Rhee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Regulatory Networks ◽  
Expression Patterns ◽  
Cell Types ◽  
Regulatory Mechanisms ◽  
Trophoblast Stem Cells ◽  
Healthy Pregnancy ◽  
Trophoblast Stem ◽  
Super Enhancer ◽  
Transcriptional Regulatory

Abstract Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.

scholarly journals Micropattern differentiation of mouse pluripotent stem cells recapitulates embryo regionalized cell fate patterning

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sophie M Morgani ◽  
Jakob J Metzger ◽  
Jennifer Nichols ◽  
Eric D Siggia ◽  
Anna-Katerina Hadjantonakis
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Fate Specification ◽  
Epiblast Stem Cells

During gastrulation epiblast cells exit pluripotency as they specify and spatially arrange the three germ layers of the embryo. Similarly, human pluripotent stem cells (PSCs) undergo spatially organized fate specification on micropatterned surfaces. Since in vivo validation is not possible for the human, we developed a mouse PSC micropattern system and, with direct comparisons to mouse embryos, reveal the robust specification of distinct regional identities. BMP, WNT, ACTIVIN and FGF directed mouse epiblast-like cells to undergo an epithelial-to-mesenchymal transition and radially pattern posterior mesoderm fates. Conversely, WNT, ACTIVIN and FGF patterned anterior identities, including definitive endoderm. By contrast, epiblast stem cells, a developmentally advanced state, only specified anterior identities, but without patterning. The mouse micropattern system offers a robust scalable method to generate regionalized cell types present in vivo, resolve how signals promote distinct identities and generate patterns, and compare mechanisms operating in vivo and in vitro and across species.

scholarly journals Laminin is the ECM niche for trophoblast stem cells

2020 ◽  
Vol 3 (2) ◽  
pp. e201900515 ◽  
Author(s):  
Daiji Kiyozumi ◽  
Itsuko Nakano ◽  
Ryoko Sato-Nishiuchi ◽  
Satoshi Tanaka ◽  
Kiyotoshi Sekiguchi
Keyword(s):  
Stem Cells ◽  
Dependent Manner ◽  
Trophoblast Stem Cells ◽  
Stem Cell Maintenance ◽  
Trophoblast Stem ◽  
Integrin Ligands ◽  
Integrin Ligand ◽  
Proliferation In Vitro

The niche is a specialized microenvironment for tissue stem cells in vivo. It has long been emphasized that niche ECM molecules act on tissue stem cells to regulate their behavior, but the molecular entities of these interactions remain to be fully elucidated. Here, we report that laminin forms the in vivo ECM niche for trophoblast stem cells (TSCs), the tissue stem cells of the placenta. TSCs expressed fibronectin-binding, vitronectin-binding, and laminin-binding integrins, whereas the integrin ligands present in the TSC niche were collagen and laminin. Therefore, the only niche integrin ligand available for TSCs in vivo was laminin. Laminin promoted TSC adhesion and proliferation in vitro in an integrin binding–dependent manner. Importantly, when the integrin-binding ability of laminin was genetically ablated in mice, the size of the TSC population was significantly reduced compared with that in control mice. The present findings underscore an ECM niche function of laminin to support tissue stem cell maintenance in vivo.

scholarly journals Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila

2021 ◽  
Vol 9 ◽  
Author(s):  
Satish Kumar Tiwari ◽  
Sudip Mandal
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Types ◽  
Extrinsic Factors ◽  
Cell Fate Decisions ◽  
Cell State ◽  
Resident Stem Cells ◽  
Stem Cell State

Over the years, Drosophila has served as a wonderful genetically tractable model system to unravel various facets of tissue-resident stem cells in their microenvironment. Studies in different stem and progenitor cell types of Drosophila have led to the discovery of cell-intrinsic and extrinsic factors crucial for stem cell state and fate. Though initially touted as the ATP generating machines for carrying various cellular processes, it is now increasingly becoming clear that mitochondrial processes alone can override the cellular program of stem cells. The last few years have witnessed a surge in our understanding of mitochondria’s contribution to governing different stem cell properties in their subtissular niches in Drosophila. Through this review, we intend to sum up and highlight the outcome of these in vivo studies that implicate mitochondria as a central regulator of stem cell fate decisions; to find the commonalities and uniqueness associated with these regulatory mechanisms.

scholarly journals Cellular Dynamics of Mouse Trophoblast Stem Cells: Identification of a Persistent Stem Cell Type1

2016 ◽  
Vol 94 (6) ◽  
Author(s):  
Kaori Motomura ◽  
Mami Oikawa ◽  
Michiko Hirose ◽  
Arata Honda ◽  
Sumie Togayachi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Biology ◽  
Expression Profiles ◽  
Single Type ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Differential Expression Pattern

Abstract Mouse trophoblast stem cells (TSCs) proliferate indefinitely in vitro, despite their highly heterogeneous nature. In this study, we sought to characterize TSC colony types by using methods based on cell biology and biochemistry for a better understanding of how TSCs are maintained over multiple passages. Colonies of TSCs could be classified into four major types: type 1 is compact and dome-shaped, type 4 is flattened but with a large multilayered cell cluster, and types 2 and 3 are their intermediates. A time-lapse analysis indicated that type 1 colonies predominantly appeared after passaging, and a single type 1 colony gave rise to all other types. These colony transitions were irreversible, but at least some type 1 colonies persisted throughout culture. The typical cells comprising type 1 colonies were small and highly motile, and they aggregated together to form primary colonies. A hierarchical clustering based on global gene expression profiles suggested that a TSC line containing more type 1 colony cells was similar to in vivo extraembryonic tissues. Among the known TSC genes examined, Elf5 showed a differential expression pattern according to colony type, indicating that this gene might be a reliable marker of undifferentiated TSCs. When aggregated with fertilized embryos, cells from types 1 and 2, but not from type 4, distributed to the polar trophectoderm in blastocysts. These findings indicate that cells typically found in type 1 colonies can persist indefinitely as stem cells and are responsible for the maintenance of TSC lines. They may provide key information for future improvements in the quality of TSC lines.

scholarly journals Retinoic Acid Promotes Differentiation of Trophoblast Stem Cells to a Giant Cell Fate

2001 ◽  
Vol 235 (2) ◽  
pp. 422-432 ◽  
Author(s):  
Junli Yan ◽  
Satoshi Tanaka ◽  
Mayumi Oda ◽  
Tsunehisa Makino ◽  
Jun Ohgane ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Giant Cell ◽  
Cell Fate ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

scholarly journals In Vivo Chromatin Targets of the Transcription Factor Yin Yang 2 in Trophoblast Stem Cells

PLoS ONE ◽  
2016 ◽  
Vol 11 (5) ◽  
pp. e0154268 ◽  
Author(s):  
Raquel Pérez-Palacios ◽  
Sofía Macías-Redondo ◽  
María Climent ◽  
Bruno Contreras-Moreira ◽  
Pedro Muniesa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Yin Yang

scholarly journals The neural crest stem cells: control of neural crest cell fate and plasticity by endothelin-3

2001 ◽  
Vol 73 (4) ◽  
pp. 533-545 ◽  
Author(s):  
ELISABETH DUPIN ◽  
CARLA REAL ◽  
NICOLE LeDOUARIN
Keyword(s):  
Stem Cells ◽  
Neural Crest ◽  
Cell Fate ◽  
Neural Crest Cell ◽  
Cell Types ◽  
The Body ◽  
Neural Crest Stem Cells ◽  
Environmental Signals

How the considerable diversity of neural crest (NC)-derived cell types arises in the vertebrate embryo has long been a key question in developmental biology. The pluripotency and plasticity of differentiation of the NC cell population has been fully documented and it is well-established that environmental cues play an important role in patterning the NC derivatives throughout the body. Over the past decade, in vivo and in vitro cellular approaches have unravelled the differentiation potentialities of single NC cells and led to the discovery of NC stem cells. Although it is clear that the final fate of individual cells is in agreement with their final position within the embryo, it has to be stressed that the NC cells that reach target sites are pluripotent and further restrictions occur only late in development. It is therefore a heterogenous collection of cells that is submitted to local environmental signals in the various NC-derived structures. Several factors were thus identified which favor the development of subsets of NC-derived cells in vitro. Moreover, the strategy of gene targeting in mouse has led at identifying new molecules able to control one or several aspects of NC cell differentiation in vivo. Endothelin peptides (and endothelin receptors) are among those. The conjunction of recent data obtained in mouse and avian embryos and reviewed here contributes to a better understanding of the action of the endothelin signaling pathway in the emergence and stability of NC-derived cell phenotypes.

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