Exploring the mechanism of pancreatic cell fate decisions via cell-cell communication

ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview.

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Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell fates in embryonic stem cells

10.1101/2020.02.14.949701 ◽

2020 ◽

Cited By ~ 4

Author(s):

Dhruv Raina ◽

Angel Stanoev ◽

Azra Bahadori ◽

Michelle Protzek ◽

Aneta Koseska ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Cell Fate ◽

Initial Conditions ◽

Embryonic Stem ◽

Cell Communication ◽

Cell Types ◽

Cell Fate Decisions ◽

Wide Range ◽

Cell Cell

AbstractDuring embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types need to be specified from homogeneous precursor cell populations. How this is achieved despite uncertainty in initial conditions in the precursor cells, and how proportions are re-established upon perturbations in the developing tissue is not known. Here we report the differentiation of robust proportions of epiblast- and primitive endoderm-like cells from a wide range of experimentally controlled initial conditions in mouse embryonic stem cells. We demonstrate both experimentally and theoretically that recursive cell-cell communication via FGF4 establishes a population-based mechanism that generates and maintains robust proportions of differentiated cell types. Furthermore, we show that cell-cell communication re-establishes heterogeneous cell identities following the isolation of one cell type. The generation and maintenance of robust cell fate proportions is a new function for FGF signaling that may extend to other cell fate decisions.

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SyNPL: Synthetic Notch pluripotent cell lines to monitor and manipulate cell interactions in vitro and in vivo

10.1101/2021.09.24.461672 ◽

2021 ◽

Author(s):

Mattias Malaguti ◽

Rosa Portero Migueles ◽

Jennifer Annoh ◽

Daina Sadurska ◽

Guillaume Blin ◽

...

Keyword(s):

Cell Fate ◽

Cell Lines ◽

Modular Design ◽

Cell Interactions ◽

Cell Populations ◽

Cell Contact ◽

Pluripotent Cells ◽

Cell Fate Decisions ◽

Cell Cell

ABSTRACTCell-cell interactions govern differentiation and cell competition in pluripotent cells during early development, but the investigation of such processes is hindered by a lack of efficient analysis tools. Here we introduce SyNPL: clonal pluripotent stem cell lines which employ optimised Synthetic Notch (SynNotch) technology to report cell-cell interactions between engineered “sender” and “receiver” cells in cultured pluripotent cells and chimaeric mouse embryos. A modular design makes it straightforward to adapt the system for programming differentiation decisions non-cell-autonomously in receiver cells in response to direct contact with sender cells. We demonstrate the utility of this system by enforcing neuronal differentiation at the boundary between two cell populations. In summary, we provide a new tool which could be used to identify cell interactions and to profile changes in gene or protein expression that result from direct cell-cell contact with defined cell populations in culture and in early embryos, and which can be adapted to generate synthetic patterning of cell fate decisions.

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Differential expression of Notch component and effector genes during ovarian follicle and corpus luteum development during the oestrous cycle

Reproduction Fertility and Development ◽

10.1071/rd13399 ◽

2015 ◽

Vol 27 (7) ◽

pp. 1038 ◽

Cited By ~ 14

Author(s):

D. Murta ◽

M. Batista ◽

E. Silva ◽

A. Trindade ◽

L. Mateus ◽

...

Keyword(s):

Corpus Luteum ◽

Cell Fate ◽

Ovarian Follicle ◽

Expression Patterns ◽

Cell Signalling ◽

Cell Communication ◽

Oestrous Cycle ◽

Specific Expression ◽

Cell Fate Decisions ◽

Effector Genes

Ovarian dynamics throughout the female oestrous cycle (EC) are characterised by cyclical follicle and corpus luteum (CL) development. These events are tightly regulated, involving extensive cell-to-cell communication. Notch is an evolutionarily well conserved cell-signalling pathway implicated in cell-fate decisions in several tissues. Here, we evaluated the extra-vascular expression patterns of Notch component and effector genes during follicle and CL development throughout the EC. Five mature CD1 female mice were killed at each EC stage. Blood samples were collected for progesterone measurement, ovaries were processed for immunohistochemistry and expression patterns of Notch components (Notch1, 2 and 3, Jagged1 and Delta-like1 and 4) and effectors (Hes1, Hes2 and Hes5) were characterised. Nuclear detection of Notch effectors indicates that Notch signalling is active in the ovary. Notch components and effectors are differentially expressed during follicle and CL development throughout the EC. The spatial and temporal specific expression patterns are associated with follicle growth, selection and ovulation or atresia and CL development and regression.

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Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster

The Journal of Cell Biology ◽

10.1083/jcb.200805001 ◽

2008 ◽

Vol 182 (6) ◽

pp. 1113-1125 ◽

Cited By ~ 55

Author(s):

An-Chi Tien ◽

Akhila Rajan ◽

Karen L. Schulze ◽

Hyung Don Ryoo ◽

Melih Acar ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Notch Signaling ◽

Cell Fate ◽

Disulfide Bonds ◽

Cell Communication ◽

Notch Receptor ◽

Cell Fate Decisions ◽

Unfolded Protein ◽

Thiol Oxidase ◽

The Unfolded Protein Response

Notch-mediated cell–cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1–like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor.

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Activity of the β-catenin phosphodestruction complex at cell–cell contacts is enhanced by cadherin-based adhesion

The Journal of Cell Biology ◽

10.1083/jcb.200811108 ◽

2009 ◽

Vol 186 (2) ◽

pp. 219-228 ◽

Cited By ~ 97

Author(s):

Meghan T. Maher ◽

Annette S. Flozak ◽

Adam M. Stocker ◽

Anjen Chenn ◽

Cara J. Gottardi

Keyword(s):

Transcription Factors ◽

Cell Adhesion ◽

Cell Fate ◽

Cell Contacts ◽

Cell Fate Decisions ◽

T Cell Factor ◽

Protein Levels ◽

Gsk 3Β ◽

Canonical Wnt ◽

Cell Cell

It is well established that cadherin protein levels impact canonical Wnt signaling through binding and sequestering β-catenin (β-cat) from T-cell factor family transcription factors. Whether changes in intercellular adhesion can affect β-cat signaling and the mechanism through which this occurs has remained unresolved. We show that axin, APC2, GSK-3β and N-terminally phosphorylated forms of β-cat can localize to cell–cell contacts in a complex that is molecularly distinct from the cadherin–catenin adhesive complex. Nonetheless, cadherins can promote the N-terminal phosphorylation of β-cat, and cell–cell adhesion increases the turnover of cytosolic β-cat. Together, these data suggest that cadherin-based cell–cell adhesion limits Wnt signals by promoting the activity of a junction-localized β-cat phosphodestruction complex, which may be relevant to tissue morphogenesis and cell fate decisions during development.

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Cell- and non-cell-autonomous ARF3 coordinates meristem proliferation and organ patterning in Arabidopsis

10.1101/2022.01.12.476103 ◽

2022 ◽

Author(s):

Xigang Liu ◽

Ke Zhang ◽

Hao Zhang ◽

Yanyun Pan ◽

Lin Guo ◽

...

Keyword(s):

Cell Fate ◽

Cell Communication ◽

Coordination Mechanism ◽

Cytokinin Activity ◽

Cytokinin Signaling ◽

Expression Domain ◽

Accumulation Pattern ◽

Organizing Center ◽

Meristem Maintenance ◽

Cell Cell

In cell-cell communication, non-cell-autonomous transcription factors play vital roles in controlling plant stem cell fate. We previously reported that AUXIN RESPONSE FACTOR 3 (ARF3), a member of the ARF family with critical roles in floral meristem maintenance and determinacy, has a distinct accumulation pattern that differs from the expression domain of its encoding gene in the shoot apical meristem (SAM). However, the biological meaning of this difference is obscure. Here, we demonstrate that ARF3 expression is mainly activated at the periphery of the SAM by auxin, where ARF3 cell-autonomously regulates the expression of meristem-organ boundary-specific genes, such as CUP-SHAPED COTYLEDON1-3 (CUC1-3), BLADE ON PETIOLE1-2 (BOP1-2) and TARGETS UNDER ETTIN CONTROL3 (TEC3) to determine organ patterning. We also show that ARF3 is translocated into the organizing center, where it represses cytokinin activity and WUSCHEL expression to regulate meristem activity non-cell-autonomously. Therefore, ARF3 acts as a molecular link that mediates the interaction of auxin and cytokinin signaling in the SAM while coordinating the balance between meristem maintenance and organogenesis. Our findings reveal an ARF3-mediated coordination mechanism through cell-cell communication in dynamic SAM maintenance.

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Pannexin 1 influences lineage specification of human iPSCs

10.1101/2021.01.21.427632 ◽

2021 ◽

Author(s):

Rebecca J. Noort ◽

Grace A. Christopher ◽

Jessica L. Esseltine

Keyword(s):

Cell Fate ◽

Cell Communication ◽

Cell Lineage ◽

The Body ◽

Human Embryos ◽

Lineage Specification ◽

Cell Stage ◽

Cell Fate Decisions ◽

Pannexin 1 ◽

Human Ipscs

AbstractEvery single cell in the body communicates with nearby cells to locally organize activities with their neighbors and dysfunctional cell-cell communication can be detrimental during cell lineage commitment, tissue patterning and organ development. Pannexin channels (PANX1, PANX2, PANX3) facilitate purinergic paracrine signaling through the passage of messenger molecules out of cells. PANX1 is widely expressed throughout the body and has recently been identified in human oocytes as well as 2 and 4-cell stage human embryos. Given its abundance across multiple adult tissues and its expression at the earliest stages of human development, we sought to understand whether PANX1 impacts human induced pluripotent stem cells (iPSCs) or plays a role in cell fate decisions. Western blot, immunofluorescence and flow cytometry reveal that PANX1 is expressed in iPSCs as well as all three germ lineages derived from these cells: ectoderm, endoderm, and mesoderm. PANX1 demonstrates differential glycosylation patterns and subcellular localization across the germ lineages. Using CRISPR-Cas9 gene ablation, we find that loss of PANX1 has no obvious impact on iPSC morphology, survival, or pluripotency gene expression. However, PANX1 knockout iPSCs exhibit apparent lineage specification bias during 2-dimensional and 3-dimensional spontaneous differentiation into the three germ lineages. Indeed, loss of PANX1 significantly decreases the proportion of ectodermal cells within spontaneously differentiated cultures, while endodermal and mesodermal representation is increased in PANX1 knockout cells. Importantly, PANX1 knockout iPSCs are fully capable of differentiating toward each specific lineage when exposed to the appropriate external signaling pressures, suggesting that although PANX1 influences germ lineage specification, it is not essential to this process.Graphical abstract

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Role of metabolic spatiotemporal dynamics in regulating biofilm colony expansion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1706920115 ◽

2018 ◽

Vol 115 (16) ◽

pp. 4288-4293 ◽

Cited By ~ 8

Author(s):

Federico Bocci ◽

Yoko Suzuki ◽

Mingyang Lu ◽

José N. Onuchic

Keyword(s):

Cell Fate ◽

Biological Networks ◽

Cell Communication ◽

Spatiotemporal Dynamics ◽

Cell Populations ◽

Modeling Framework ◽

Oscillatory Dynamics ◽

Oscillatory Dynamic ◽

Cell Cell

Cell fate determination is typically regulated by biological networks, yet increasing evidences suggest that cell−cell communication and environmental stresses play crucial roles in the behavior of a cell population. A recent microfluidic experiment showed that the metabolic codependence of two cell populations generates a collective oscillatory dynamic during the expansion of aBacillus subtilisbiofilm. We develop a modeling framework for the spatiotemporal dynamics of the associated metabolic circuit for cells in a colony. We elucidate the role of metabolite diffusion and the need of two distinct cell populations to observe oscillations. Uniquely, this description captures the onset and thereafter stable oscillatory dynamics during expansion and predicts the existence of damping oscillations under various environmental conditions. This modeling scheme provides insights to understand how cells integrate the information from external signaling and cell−cell communication to determine the optimal survival strategy and/or maximize cell fitness in a multicellular system.

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KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development

The Journal of Cell Biology ◽

10.1083/jcb.140.6.1519 ◽

1998 ◽

Vol 140 (6) ◽

pp. 1519-1534 ◽

Cited By ~ 69

Author(s):

V. Cirulli ◽

L. Crisa ◽

G.M. Beattie ◽

M.I. Mally ◽

A.D. Lopez ◽

...

Keyword(s):

Cell Adhesion ◽

Cell Growth ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Fate ◽

Pancreatic Islet ◽

Pancreatic Cell ◽

Cell Clusters ◽

Endocrine Differentiation ◽

Cell Cell

Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell–cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny.

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