Spatiotemporal profiling of adhesion G protein-coupled receptors in developing mouse and human pancreas reveals a role for GPR56 in islet development DOI Creative Commons
Oladapo E. Olaniru,

Klaudia Toczyska,

Nunzio Guccio

et al.

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: March 26, 2025

G protein-coupled receptors (GPCRs) are cell-surface proteins that targeted therapeutically for a range of disorders, including diabetes. Adhesion GPCRs (aGPCRs) the second largest class GPCR superfamily and some members this family have been implicated in appropriate organ development. However, role aGPCRs endocrine pancreas specification is not yet known. Here, we systematically characterised expression mRNAs encoding their ligands developing mouse human using our own publicly available single-cell RNA sequencing spatial transcriptomics data, conducted qPCR analysis aGPCR at different gestational stages. We then investigated GPR56 (ADGRG1), most abundant pancreatic progenitors, islet development Gpr56 null mice wildtype littermates. demonstrated dynamically expressed during development, with specific distinct endocrine, endothelial, mesenchymal, acinar, ductal, immune cell clusters. ligand were mostly by non-endocrine cells, highly receptor-ligand interacting mRNA pairs those COL3A1. Deletion neonatal was associated an altered α-/β-/δ-cell ratio reduced β-cell proliferation. Our data show key stages lineage decisions, pancreases from knockout implicate full complement β-cells.

Language: Английский

Integrative spatial analysis reveals a multi-layered organization of glioblastoma DOI Creative Commons
Alissa C. Greenwald,

Noam Galili Darnell,

Rouven Hoefflin

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(10), P. 2485 - 2501.e26

Published: April 22, 2024

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, proteomics, and computational approaches to define glioma cellular states uncover their organization. We find three prominent modes of First, gliomas are composed small local environments, each typically enriched with one major state. Second, specific pairs preferentially reside proximity across multiple scales. This pairing is consistent tumors. Third, these pairwise interactions collectively a global architecture five layers. Hypoxia appears drive the layers, as it associated long-range organization that includes all cancer cell Accordingly, tumor regions distant from any hypoxic/necrotic foci tumors lack hypoxia such low-grade IDH-mutant less organized. In summary, provide conceptual framework for glioma, highlighting tissue organizer.

Language: Английский

Citations

78
Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions DOI Creative Commons
Eileen S. Carpenter, Ahmed M. Elhossiny, Padma Kadiyala

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(6), P. 1324 - 1345

Published: April 6, 2023

Abstract The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from in absence disease and rapid postmortem degradation. We obtained pancreata brain dead donors, thus avoiding any warm ischemia time. 30 donors were diverse age race had no known disease. Histopathologic analysis samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions most individuals irrespective age. Using a combination multiplex IHC, single-cell RNA sequencing, spatial transcriptomics, we provide first-ever characterization unique microenvironment sporadic PanIN lesions. compared cancer peritumoral observed distinct transcriptomic signatures fibroblasts and, lesser extent, macrophages. epithelial cells remarkably transcriptionally similar cells, suggesting that neoplastic pathways are initiated early tumorigenesis. Significance: Precursor characterized. analyzed donor discovered precursor detected at much higher rate than incidence cancer, setting stage for efforts elucidate microenvironmental cell-intrinsic factors restrain or, conversely, promote malignant progression. See related commentary by Hoffman Dougan, p. 1288. This article is highlighted In Issue feature, 1275

Language: Английский

Citations

63
Single-cell sequencing to multi-omics: technologies and applications DOI Creative Commons
Xiangyu Wu, Xin Yang,

Yunhan Dai

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Sept. 27, 2024

Abstract Cells, as the fundamental units of life, contain multidimensional spatiotemporal information. Single-cell RNA sequencing (scRNA-seq) is revolutionizing biomedical science by analyzing cellular state and intercellular heterogeneity. Undoubtedly, single-cell transcriptomics has emerged one most vibrant research fields today. With optimization innovation technologies, intricate details concealed within cells are gradually unveiled. The combination scRNA-seq other multi-omics at forefront field. This involves simultaneously measuring various omics data individual cells, expanding our understanding across a broader spectrum dimensions. precisely captures aspects transcriptomes, immune repertoire, spatial information, temporal epitopes, in diverse contexts. In addition to depicting cell atlas normal or diseased tissues, it also provides cornerstone for studying differentiation development patterns, disease heterogeneity, drug resistance mechanisms, treatment strategies. Herein, we review traditional technologies outline latest advancements multi-omics. We summarize current status challenges applying biological clinical applications. Finally, discuss limitations potential strategies address them.

Language: Английский

Citations

21
Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions DOI
Zhiwei Cai, Hong-Fei Yao, Jiahao Chen

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216689 - 216689

Published: Feb. 15, 2024

Language: Английский

Citations

19
Spatial transcriptomics in development and disease DOI Creative Commons
Ran Zhou,

Gaoxia Yang,

Yan Zhang

et al.

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 9, 2023

Abstract The proper functioning of diverse biological systems depends on the spatial organization their cells, a critical factor for processes like shaping intricate tissue functions and precisely determining cell fate. Nonetheless, conventional bulk or single-cell RNA sequencing methods were incapable simultaneously capturing both gene expression profiles locations cells. Hence, multitude spatially resolved technologies have emerged, offering novel dimension investigating regional expression, domains, interactions between Spatial transcriptomics (ST) is method that maps in while preserving information. It can reveal cellular heterogeneity, functional complex systems. ST also complement integrate with other omics to provide more comprehensive holistic view at multiple levels resolution. Since advent ST, new higher throughput resolution become available, holding significant potential expedite fresh insights into comprehending complexity. Consequently, rapid increase associated research has occurred, using these unravel complexity during developmental disease conditions. In this review, we summarize recent advancement historical, technical, application contexts. We compare different types based principles workflows, present bioinformatics tools analyzing integrating data modalities. highlight applications various domains biomedical research, especially development diseases. Finally, discuss current limitations challenges field, propose future directions ST.

Language: Английский

Citations

27
Exploring pancreatic beta-cell subgroups and their connectivity DOI Creative Commons
Guy A. Rutter, Anne Gresch, Luis Fernando Delgadillo-Silva

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(11), P. 2039 - 2053

Published: Aug. 8, 2024

Language: Английский

Citations

10
Pancreatic organogenesis mapped through space and time DOI Creative Commons
Marissa A. Scavuzzo, Wojciech J. Szlachcic, Matthew C. Hill

et al.

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract The spatial organization of cells within a tissue is dictated throughout dynamic developmental processes. We sought to understand whether geometrically coordinate with one another development achieve their organization. pancreas complex cellular organ particular Signals from the mesenchyme, neurons, and endothelial instruct epithelial cell differentiation during pancreatic development. To diversity developing niche, we mapped relationships between single over time. found that four transcriptionally unique subtypes mesenchyme in spatially development, each subtype at fixed locations space time relation other cells, including beta vasculature, cells. Our work provides insight into mechanisms by showing are organized manner.

Language: Английский

Citations

1
Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage DOI Creative Commons
Mayur Doke,

Silvia Álvarez-Cubela,

Dagmar Klein

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(11), P. 1944 - 1960.e7

Published: Oct. 27, 2023

Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture human slices (HPSs) presented field with an opportunity dynamically track tissue at level. Combining same-donor HPSs different time points, or without known regenerative stimulus (BMP signaling), led integrated storing true temporal treatment-dependent information. This integration revealed population shifts consistent ductal progenitor activation, blurring ductal/acinar boundaries, formation ducto-acinar-endocrine differentiation axes, and detection transitional insulin-producing cells. study provides first longitudinal scRNA-seq whole tissue, confirming its dynamic fashion.

Language: Английский

Citations

20
Integrative spatial analysis reveals a multi-layered organization of glioblastoma DOI Creative Commons
Alissa C. Greenwald,

Noam Galili Darnell,

Rouven Hoefflin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 8, 2023

Summary Glioma contains malignant cells in diverse states. Hypoxic regions are associated with a unique histology of pseudopalisading cells, while other appear to have limited histological organization, reflecting the diffuse nature glioma cells. Here, we combine spatial transcriptomics proteomics and novel computational approaches define cellular states at high granularity uncover their organization. We find three prominent modes First, any given state tend be spatially clustered, such that tumors composed small local environments each typically enriched one major state. Second, specific pairs preferentially reside proximity across multiple scales. Despite composition tumor, this pairing remains largely consistent tumors. Third, pairwise interactions detect collectively global architecture five layers. Hypoxia appears drive 5-layered as it is both surrounding long-range organization extends from hypoxic core infiltrative edge tumor. Accordingly, tumor distant foci lack hypoxia IDH-mutant less organized. In summary, provide conceptual framework for gliomas resolution highlight role tissue organizer.

Language: Английский

Citations

12
ISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models DOI Creative Commons
Rui Hu, Xiangyi Chen, Qiang Su

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(3), P. 322 - 334

Published: Feb. 6, 2024

Abstract Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model WS has impeded progress the development new treatments. Here, pluripotent stem cell derived pancreatic islets (SC-islets) harboring and mouse β specific Wfs1 knockout were applied to WS. We charted high-resolution roadmap single-cell RNA-seq (scRNA-seq) investigate pathogenesis for failure, revealing two distinct cellular fates along pseudotime trajectory: maturation stress branches. disrupted fate trajectory toward directed it towards trajectory, ultimately leading failure. Notably, further investigation identified activated integrated response (ISR) as crucial mechanism underlying characterized aberrant eIF2 signaling -deficient SC-islets, elevated expression genes regulating granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed SC-islets. validated therapeutic efficacy vivo mice. Altogether, our study provides novel insights into offers strategy targeting treat diabetes.

Language: Английский

Citations

4