scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

scholarly journals An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation

2021 ◽  
Vol 9 ◽  
Author(s):  
Sakshi Khurana ◽  
Stefano Schivo ◽  
Jacqueline R. M. Plass ◽  
Nikolas Mersinis ◽  
Jetse Scholma ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Model Checking ◽  
Cell Fate ◽  
Growth Plate ◽  
Ex Vivo ◽  
Boolean Model ◽  
Zonal Distribution ◽  
Cell Fate Decisions ◽  
Hypertrophic Cartilage ◽  
Cartilage Formation

A fundamental question in cartilage biology is: what determines the switch between permanent cartilage found in the articular joints and transient hypertrophic cartilage that functions as a template for bone? This switch is observed both in a subset of OA patients that develop osteophytes, as well as in cell-based tissue engineering strategies for joint repair. A thorough understanding of the mechanisms regulating cell fate provides opportunities for treatment of cartilage disease and tissue engineering strategies. The objective of this study was to understand the mechanisms that regulate the switch between permanent and transient cartilage using a computational model of chondrocytes, ECHO. To investigate large signaling networks that regulate cell fate decisions, we developed the software tool ANIMO, Analysis of Networks with interactive Modeling. In ANIMO, we generated an activity network integrating 7 signal transduction pathways resulting in a network containing over 50 proteins with 200 interactions. We called this model ECHO, for executable chondrocyte. Previously, we showed that ECHO could be used to characterize mechanisms of cell fate decisions. ECHO was first developed based on a Boolean model of growth plate. Here, we show how the growth plate Boolean model was translated to ANIMO and how we adapted the topology and parameters to generate an articular cartilage model. In ANIMO, many combinations of overactivation/knockout were tested that result in a switch between permanent cartilage (SOX9+) and transient, hypertrophic cartilage (RUNX2+). We used model checking to prioritize combination treatments for wet-lab validation. Three combinatorial treatments were chosen and tested on metatarsals from 1-day old rat pups that were treated for 6 days. We found that a combination of IGF1 with inhibition of ERK1/2 had a positive effect on cartilage formation and growth, whereas activation of DLX5 combined with inhibition of PKA had a negative effect on cartilage formation and growth and resulted in increased cartilage hypertrophy. We show that our model describes cartilage formation, and that model checking can aid in choosing and prioritizing combinatorial treatments that interfere with normal cartilage development. Here we show that combinatorial treatments induce changes in the zonal distribution of cartilage, indication possible switches in cell fate. This indicates that simulations in ECHO aid in describing pathologies in which switches between cell fates are observed, such as OA.

scholarly journals Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

2019 ◽  
Vol 20 (2) ◽  
pp. 455 ◽  
Author(s):  
Felix Beyer ◽  
Iria Samper Agrelo ◽  
Patrick Küry
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Cell Types ◽  
Adult Brain ◽  
Repair Capacity ◽  
Cell Fate Decisions ◽  
Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

scholarly journals Decoding of position in the developing neural tube from antiparallel morphogen gradients

Science ◽  
2017 ◽  
Vol 356 (6345) ◽  
pp. 1379-1383 ◽  
Author(s):  
Marcin Zagorski ◽  
Yoji Tabata ◽  
Nathalie Brandenberg ◽  
Matthias P. Lutolf ◽  
Gašper Tkačik ◽  
...  
Keyword(s):  
Pattern Formation ◽  
Cell Fate ◽  
Neural Tube ◽  
Target Gene ◽  
Ex Vivo ◽  
Data Link ◽  
Cell Fate Decisions ◽  
Morphogen Gradients ◽  
Positional Identity ◽  
Mechanistic Basis

Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. To understand how these inputs are interpreted, we measured morphogen signaling and target gene expression in mouse embryos and chick ex vivo assays. From these data, we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. Analysis of the observed responses indicates that the underlying interpretation strategy minimizes patterning errors in response to the joint input of noisy opposing gradients. We reverse-engineered a transcriptional network that provides a mechanistic basis for the observed cell fate decisions and accounts for the precision and dynamics of pattern formation. Together, our data link opposing gradient dynamics in a growing tissue to precise pattern formation.

scholarly journals Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

2018 ◽  
Author(s):  
Daniel Strebinger ◽  
Cédric Deluz ◽  
Elias T. Friman ◽  
Subashika Govindan ◽  
Andrea B. Alber ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Directed Differentiation ◽  
Es Cell ◽  
Endogenous Fluctuations ◽  
Cell Fate Decisions ◽  
Oct4 Protein

AbstractSOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. However, how temporal fluctuations in their expression levels bias lineage commitment is unknown. Here we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cell towards both neuroectodermal and mesendodermal fates. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.

scholarly journals The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

2021 ◽  
Author(s):  
Josh Saul ◽  
Takashi Hirose ◽  
Robert Horvitz
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Transcriptional Corepressor ◽  
Cell Identity ◽  
C Elegans ◽  
Dna Binding Specificity ◽  
A Cell ◽  
Transcriptional Corepressors ◽  
And Function

Cell identity is characterized by a distinct combination of gene expression, cell morphology and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here we show that the gene ctbp-1, which encodes the transcriptional corepressor C-terminal binding protein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in older worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

Bioinspired in vitro microenvironments to control cell fate: Focus on macromolecular crowding

2021 ◽  
Author(s):  
Dimitrios I. Zeugolis
Keyword(s):  
Cell Fate ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Control Cell ◽  
Macromolecular Crowding ◽  
Cell Phenotype ◽  
Cell Culture Systems ◽  
And Function ◽  
Phenotypic Drift

The development of therapeutic regenerative medicine and accurate drug discovery cell-based products requires effective, with respect to obtaining sufficient numbers of viable, proliferative and functional cell populations, cell expansion ex vivo. Unfortunately, traditional cell culture systems fail to recapitulate the multifaceted tissue milieu in vitro, resulting in cell phenotypic drift, loss of functionality, senescence and apoptosis. Substrate-, environmental- and media- induced approaches are under intense investigation as a means to maintain cell phenotype and function whilst in culture. In this context, herein, the potential of macromolecular crowding, a biophysical phenomenon with considerable biological consequences, is discussed.

Nicotinamide, a Potent SIRT2 Inhibitor, Delays Differentiation of Hematopoietic Progenitor Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4142-4142
Author(s):  
Toni Peled ◽  
Sophie Adi ◽  
Elina Glukhman ◽  
Frida Grynspan ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Cell Cultures ◽  
Ex Vivo ◽  
Cell Phenotype ◽  
Type I ◽  
Hematopoietic Stem ◽  
Additional Function ◽  
Base Exchange ◽  
Cell Fate Decisions

Abstract CD38, originally described as a differentiation marker, has emerged as an important multifunctional transmembrane protein. Its most intriguing and well-characterized function is its ability to catalyze the synthesis of cyclic ADP-ribose (cADPR) from NAD. Of particular interest is its presence on the inner membrane of the nucleus, suggesting that CD38/cADPR may play a direct role in mediating nuclear activation and gene expression. Our studies on ex vivo expansion of Hematopoietic Stem Cells (HSCs) have led us to test whether alteration of CD38 function carries the potential of affecting cell fate decisions of HSCs. Inhibition of CD38 enzymatic activity was achieved by treating CD34+ cell cultures with nicotinamide (NA), a well-known base-exchange inhibitor demonstrated to inhibit the synthesis of cADPR from NAD. We report here that exogenously added nicotinamide (5–10 mM) to CD34+ cell cultures supplemented with cytokines (SCF, TPO, IL-6, FLt3, +/− IL-3) resulted in significant enrichment of CD34+CD38− (79±9.3%, n=9) and CD34+CD38−Lin− (19±3%, n=8) cells, as compared with control cultures treated only with cytokines (6.3±1.8%, n=9, and 0.7±0.06%, n=8, respectively, p<0.01). The functionality of these early progenitor subsets was demonstrated using the extended LTC-CFC assay, performed in the absence of NA. These results raised the intriguing possibility that cADPR production may have a pivotal role in regulation of CD34+ cell fate. However, inhibition of cADPR downstream signal transduction pathways by its specific antagonist, 8-amino-cADPR did not yield any effect on CD34+ cell cultures, excluding the possibility that nicotinamide modulates CD34+ cell fate solely by inhibition of cADPR synthesis. Nicotinamide is also a well-known potent inhibitor of SIRT2, a unique NAD(+)-dependent type III histone deacetylase (HDAC) with mono-ADP-ribosyltransferase activity involved in gene silencing, metabolism, apoptosis and aging. NA blocks NAD(+) hydrolysis by binding to an adjacent conserved pocket, and is therefore suggested as the physiologically relevant regulator of SIRT2 enzymes. This additional function of nicotinamide raises the intriguing possibility that HSC enrichment achieved by nicotinamide treatment may be related to specific inhibition of SIRT2 deacetylase activity and modulation of chromatin architecture leading to re-activation of previously silenced genes. In line with this hypothesis, Milhem et all. recently reported that addition of trichostatin A, a specific HDAC (type I and II) inhibitor, along with a DNA hypomethylating agent, modulated HSC fate ex vivo resulting in the retention of stem cell phenotype, number, and function (Blood, 2004; 103; 4102). Ongoing work is aimed at elucidating whether inhibition of SIRT2 is specifically involved in NA mechanism of activity leading to modulation of hematopoietic stem cell fate in ex vivo conditions.

scholarly journals Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 676
Author(s):  
Matthew Man-Kin Wong ◽  
Sancy Mary Joyson ◽  
Heiko Hermeking ◽  
Sung Kay Chiu
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Leucine Zipper ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ex Vivo ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Cell Fate Decisions

Activating Enhancer-Binding Protein 4 (AP4)/transcription factor AP4 (TFAP4) is a basic-helix-loop-helix-leucine-zipper transcription factor that was first identified as a protein bound to SV40 promoters more than 30 years ago. Almost 15 years later, AP4 was characterized as a target of the c-Myc transcription factor, which is the product of a prototypic oncogene that is activated in the majority of tumors. Interestingly, AP4 seems to represent a central hub downstream of c-Myc and N-Myc that mediates some of their functions, such as proliferation and epithelial-mesenchymal transition (EMT). Elevated AP4 expression is associated with progression of cancer and poor patient prognosis in multiple tumor types. Deletion of AP4 in mice points to roles of AP4 in the control of stemness, tumor initiation and adaptive immunity. Interestingly, ex vivo AP4 inactivation results in increased DNA damage, senescence, and apoptosis, which may be caused by defective cell cycle progression. Here, we will summarize the roles of AP4 as a transcriptional repressor and activator of target genes and the contribution of protein and non-coding RNAs encoded by these genes, in regulating the above mentioned processes. In addition, proteins interacting with or regulating AP4 and the cellular signaling pathways altered after AP4 dysregulation in tumor cells will be discussed.

Structure and function of the human parvulins Pin1 and Par14/17

2018 ◽  
Vol 399 (2) ◽  
pp. 101-125 ◽  
Author(s):  
Anja Matena ◽  
Edisa Rehic ◽  
Dana Hönig ◽  
Bianca Kamba ◽  
Peter Bayer
Keyword(s):  
Cell Fate ◽  
Metabolic Pathways ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Current Knowledge ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
The Family ◽  
Broad Variety ◽  
And Function

AbstractParvulins belong to the family of peptidyl-prolylcis/transisomerases (PPIases) assisting in protein folding and in regulating the function of a broad variety of proteins in all branches of life. The human representatives Pin1 and Par14/17 are directly involved in processes influencing cellular maintenance and cell fate decisions such as cell-cycle progression, metabolic pathways and ribosome biogenesis. This review on human parvulins summarizes the current knowledge of these enzymes and intends to oppose the well-studied Pin1 to its less well-examined homolog human Par14/17 with respect to structure, catalytic and cellular function.

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