Biology subjects

Heyman, Y.

Publications and source records attributed to Heyman, Y..

3 recordsLinked to original sources

bioRxiv2025

Self-Organization Through Local Cell-Cell Communication Drives Intestinal Epithelial Zonation

The intestinal epithelium exhibits zonated gene expression along the crypt-villus axis, with distinct transcriptional programs in enterocytes at the villus top versus bottom. However, the mechanisms establishing these spatial patterns remain unclear. Three models could explain zonation: external gradients, cell-intrinsic temporal programs, or local self-organization. Using spatial transcriptomics and perturbations of two-dimensional intestinal organoids, we show that zonation emerges via spontaneous self-organization without mesenchymal, neural, or vascular inputs. Cell-intrinsic models were eliminated by transplanting cells into established monolayers; transplanted cells progressively adopted zonation profiles matching their new location, with strongly zonated genes showing the greatest adaptive responses. Pharmacological inhibition of EphA2 receptors disrupted zonation, revealing a previously unknown role for epithelial EphA-ephrin-A signaling in regulating enterocyte zonation. These findings demonstrate that self-organization through local epithelial cell-cell communication generates spatial patterns independently of external positional cues or cell-autonomous programs.

systems biology↗

bioRxiv2025

Single-cell spatial mapping reveals reproducible cell type organization and spatially-dependent gene expression in gastruloids

Gastruloids are stem-cell-based models that recapitulate key aspects of mammalian gastrulation, including formation of an anterior-posterior (AP) axis. However, we do not have detailed spatial information about gene expression and cell type organization, particularly at the level of individual gastruloids. Here, we report a spatially resolved, single-cell molecular catalog of the transcriptomes of 26 individual gastruloids. We found that cell type composition and tissue-scale spatial organization were largely consistent across gastruloids, but meso-scale patterning of specific cell types varied between samples. Posterior cell types formed distinct, organized clusters, while anterior cell types were more disorganized. To distinguish progressive differentiation from cell type differences, we developed the L-score, a parameter-free quantification of mutually exclusive gene expression. This analysis revealed spatial organization without explicit encoding, recapitulated known cell type relationships, and identified novel gene expression states and spatial subclusters within cell types. We confirmed that in gastruloids, NMP differentiation occurred through a continuous, spatially-coordinated process. We also showed that endothelial precursors exhibited unique spatial organization and had distinct gene expression profiles dependent on their association with anterior somitic or posterior endodermal tissues. This work enables the rigorous use of gastruloids as models for studying the molecular mechanisms underlying mammalian development and tissue organization, and introduces new computational tools for analyzing spatially-resolved single-cell datasets.

developmental biology↗

bioRxiv2025

SpaceBar enables clone tracing in spatial transcriptomic data

We report a cellular barcoding strategy, SpaceBar, that enables simultaneous clone tracing and spatial transcriptomics profiling. Our approach uses a library of 96 synthetic barcode sequences that can be robustly detected by imaging based spatial transcriptomics (seqFISH), delivered such that each cell is labeled with a combination of barcodes. We used these barcodes to label melanoma cells in a tumor xenograft model and profiled both clone identity and spatial gene expression in situ. We developed a gene scoring metric that quantifies how strongly gene expression is driven by intrinsic cellular cues or extrinsic environmental signals. Our framework distinguishes between clonal dynamics and environmentally-driven transcriptional regulation in complex tissue contexts.

genomics↗