Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids DOI Open Access
Kyoung Jo,

Zong-Yuan Liu,

Gauri Patel

et al.

Published: Nov. 8, 2024

The role of FGF is the least understood morphogens driving mammalian gastrulation. Here we investigated function in a stem cell model for human gastrulation known as 2D gastruloid. We found ring FGF-dependent ERK activity that closely follows emergence primitive streak (PS)-like cells but expands further inward. showed this pattern required PS-like differentiation and loss upon receptor inhibition can be rescued by directly activating ERK. demonstrated ERK-ring depends on localized activation basally receptors (FGFR) endogenous gradients. confirm extend previous studies analyzing expression pathway components, showing main to FGFR1 key ligands FGF2/4/17, similar monkey embryo different from mouse. In situ hybridization scRNA-seq revealed FGF4 FGF17 colocalize with PS marker TBXT only maintained nascent mesoderm endoderm. reduction both reduced their derivatives, indicating overlapping function. Thus, have identified previously unknown signaling gastruloids possibly embryo, driven mechanism where signal through induce cells.

Language: Английский

Time-integrated BMP signaling determines fate in a stem cell model for early human development DOI Creative Commons
Seth Teague, Gillian Primavera, Bohan Chen

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 17, 2024

Abstract How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development vivo and vitro remains poorly understood. Here we report an automated tracking method follow signaling histories linked large numbers of pluripotent stem cells (hPSCs). Using unbiased statistical approach, discover that measured BMP history correlates strongly with individual cells. We find response hPSCs varies more the duration than level. However, both level activity control choices only by changing time integral. Therefore, interchangeable this context. In model for patterning embryo, show predict pattern integral correctly predicts changes domains when is perturbed. Our data suggest mechanistically, integrated SOX2.

Language: Английский

Citations

21
Combinatorial interpretation of BMP and WNT controls the decision between primitive streak and extraembryonic fates DOI Creative Commons
Elena Camacho-Aguilar, Sumin Yoon,

Miguel Angel Ortiz-Salazar

et al.

Cell Systems, Journal Year: 2024, Volume and Issue: 15(5), P. 445 - 461.e4

Published: April 30, 2024

Language: Английский

Citations

7
Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs DOI Creative Commons
Mariia Minaeva, Júlia Domingo, Philipp Rentzsch

et al.

NAR Genomics and Bioinformatics, Journal Year: 2025, Volume and Issue: 7(1)

Published: Jan. 7, 2025

Abstract Understanding the role of transcription and factors (TFs) in cellular identity disease, such as cancer, is essential. However, comprehensive data resources for cell line-specific TF-to-target gene annotations are currently limited. To address this, we employed a straightforward method to define regulons that capture cell-specific aspects TF binding transcript expression levels. By integrating transcriptome data, generated 40 common lines comprising both proximal distal regulatory events. Through systematic benchmarking involving knockout experiments, demonstrated performance on par with state-of-the-art methods, our being easily applicable other types interest. We present case studies using three cancer single-cell datasets showcase utility these cell-type-specific exploring transcriptional dysregulation. In summary, this study provides valuable pipeline resource systematically regulations, emphasizing network analysis deciphering disease mechanisms.

Language: Английский

Citations

1
Morphogen Patterning in Dynamic Tissues DOI Creative Commons
Alex M. Plum, Mattia Serra

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Abstract Embryogenesis integrates morphogenesis—coordinated cell movements—with morphogen patterning and differentiation. While largely studied independently, morphogenesis often unfold simultaneously in early embryos. Yet, how movements affect remains unclear, as most pattern formation models assume static tissues. We address this gap by developing a mathematical framework for dynamic tissues, reformulating advection-reaction-diffusion cells’ reference frames—the natural signal interpretation fate decisions. This (i) elucidates mediates transport compartmentalization: multicellular attractors enhance cell-cell diffusive transport, while repellers act barriers, affecting induction bifurcations. (ii) It formalizes signaling ranges deconfounding morphogenetic identifying which cells can communicate. (iii) provides two nondimensional numbers—typically distinct from the Péclet number—to assess when where is relevant patterning. (iv) generative role of density dynamics apply to classic models, motifs, avian gastrulation data. Broadly, our work quantitative perspective rationalize tissue synthetic

Language: Английский

Citations

0
Neural plate pre-patterning enables specification of intermediate neural progenitors in the spinal cord DOI Creative Commons
Nagarajan Nandagopal,

Anna Cha,

Bill Jia

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Summary Dorsal-ventral patterning of neural progenitors in the posterior tube, which gives rise to spinal cord, has served as a model system understand how extracellular signals organize developing tissues. While previous work shown that signaling gradients diversify progenitor fates at dorsal and ventral ends tissue, basis fate specification intermediate regions remained unclear. Here we use zebrafish investigate plate, precedes tube formation, show its pre-patterning by distinct environment enables specification. Systematic spatial analysis transcription factor (TF) expression activity using reference-based mapping approach shows plate is partitioned into striking complexity TF co-expression states that, part, correspond gastrulation such FGF Wnt persist through axis extension. Using toto cellular movement combined with mapping, find dbx1b -expressing (p0) originate from neural-plate specific state characterized transient TFs pax3a , olig4 her3 . Finally, this defined ectopic activation within pax3a/olig4 + cells sufficient promote expression. Our data broadly support occurs sequential multiple progressively tissue it develops. This implications for vitro differentiation cord cell types understanding signal-based other developmental contexts.

Language: Английский

Citations

0
Anti-resonance in developmental signaling regulates cell fate decisions DOI Creative Commons
Samuel J Rosen, Olivier Witteveen, Naomi Baxter

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Cells process dynamic signaling inputs to regulate fate decisions during development. While oscillations or waves in key developmental pathways, such as Wnt, have been widely observed, the principles governing how cells decode these signals remain unclear. By leveraging optogenetic control of Wnt pathway both HEK293T and H9 human embryonic stem cells, we systematically map relationship between signal frequency downstream activation. We find that exhibit a minimal response at certain frequencies, behavior term anti-resonance. developed detailed biochemical simplified hidden variable models explain anti-resonance emerges from interplay fast slow dynamics. Remarkably, directly influences cell involved gastrulation; delivered anti-resonant frequencies result dramatically reduced mesoderm differentiation. Our work reveals previously unknown mechanism may filter against spurious These findings establish new insights into with implications for tissue engineering, regenerative medicine, cancer biology.

Language: Английский

Citations

0
HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells DOI Creative Commons

Adam T Lynch,

Naomi Phillips, Megan Douglas

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

Abstract Diverse sets of progenitors contribute to the development embryonic heart, but mechanisms their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation identified transcription factors underpinning specification, identity function. We discovered concentration-dependent, fate determining function for basic helix-loop-helix factor HAND1 mesodermal uncovered its gene regulatory network. At low expression level, directs towards multipotent juxta-cardiac field able make cardiomyocytes epicardial cells, whereas at high level it promotes extraembryonic mesoderm. Importantly, HAND1-low can be propagated state. This detailed mechanistic insight into has potential accelerate delivery effective disease modelling, including congenital heart disease, therapy-based regenerative medicine.

Language: Английский

Citations

0
Extended culture of 2D gastruloids to model human mesoderm development DOI
Bohan Chen, Hina Khan, Zhiyuan Yu

et al.

Nature Methods, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Language: Английский

Citations

0
Deciphering the history of ERK activity from fixed-cell immunofluorescence measurements DOI Creative Commons
Abhineet Ram, Michael Pargett,

Yongin Choi

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 21, 2025

Abstract The RAS/ERK pathway plays a central role in diagnosis and therapy for many cancers. ERK activity is highly dynamic within individual cells drives cell proliferation, metabolism, other processes through effector proteins including c-Myc, c-Fos, Fra-1, Egr-1. These are sensitive to the dynamics of activity, but it not clear what extent pattern an determines protein expression, or how much information about embedded expression. Here, we evaluate these relationships using live-cell biosensor measurements multiplexed with immunofluorescence staining downstream target pathway. Combining datasets linear regression, machine learning, differential equation models, develop interpretive framework data, wherein Fra-1 pRb levels imply long-term activation signaling, while Egr-1 c-Myc indicate more recent activation. Analysis multiple cancer lines reveals distorted relationship between state malignant cells. We show that this can infer various classes from stains heterogeneous population, providing basis annotating fixed

Language: Английский

Citations

0
Linking Single-Cell Dynamics to Cell Fate in Differentiating hPSCs DOI
Seth Teague, Zhiyuan Yu, Idse Heemskerk

et al.

Methods in molecular biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0