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Single-Cell and Spatial Multi-Omics in Human Diseases
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Single-Cell and Spatial Multi-Omics in Human Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Bioinformatics".

Deadline for manuscript submissions: 25 December 2025 | Viewed by 2086

Special Issue Editor

Dr. Xin Wang

E-Mail Website
Guest Editor
Kidney and Urinary Tract Center, Nationwide Children’s Hospital, Columbus, OH 43221, USA
Interests: cancer immunotherapy; kidney disease; single-cell omics; aging; DNA double-strand break repair; templated insertion; spatial transcriptomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The recent breakthrough in high-throughput omics technologies has revolutionized our understanding of human biology and disease. The emerging single-cell and spatial multi-omics have provided a holistic view of the cellular composition and molecular landscape within tissues at a single-cell resolution in a spatial context. These advancements, transitioning from bulk tissue or cell type to single-cell and spatial levels, have unlocked a wide variety of novel biological discoveries, such as the intricate interplay between gene expression, cellular heterozygosity, the microenvironment and disease pathogenesis. These technologies have become hallmarks of single-cell omics and multi-cellular-resolution spatial techniques, supported by significantly advanced analytical tools. To date, more than 63 million cells from 9.2K donors have been profiled across various human tissues. High-resolution transcriptomics and spatial atlases have been developed to study both healthy humans and those with diseases, such as adult human heart and ischemic heart disease, human kidney disease (acute kidney injury, chronic kidney disease, diabetes, and hypertension), and breast cancer (triple-negative breast cancer, metastatic breast cancer). These studies reveal the cellular complexity of the microenvironment and highlight the clinical prognostic value of spatial data. While these efforts have generated vast datasets, they require sophisticated analyses to navigate the complexities across molecular, cellular, and spatiotemporal scales. The achievements presented in this particular Special Issue can pave the way for uncovering disease mechanisms, improving patient outcomes, and advancing integrated knowledge in human health.

This Special Issue of Genes welcomes reviews and original papers covering recent genetic research on any type of single-cell or nuclei spatial genomics, transcriptomics, and epigenetics in human diseases or mouse models. Special interest will be given to integrative single-cell omics studies.

Dr. Xin Wang
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • single-cell omics
  • spatial multi-omics
  • pathogenesis of disease
  • biomarkers
  • computational tools
  • integrative biology

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Published Papers (2 papers)

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Research

18 pages, 7687 KiB  
Article
Construction of Gene Regulatory Networks Based on Spatial Multi-Omics Data and Application in Tumor-Boundary Analysis
by Yiwen Du, Kun Xu, Siwen Zhang, Lanming Chen, Zhenhao Liu and Lu Xie
Genes 2025, 16(7), 821; https://doi.org/10.3390/genes16070821 - 13 Jul 2025
Viewed by 848
Abstract
Background/Objectives: Cell–cell communication (CCC) is a critical process within the tumor microenvironment, governing regulatory interactions between cancer cells and other cellular subpopulations. Aiming to improve the accuracy and completeness of intercellular gene-regulatory network inference, we constructed a novel spatial-resolved gene-regulatory network framework (spGRN). [...] Read more.
Background/Objectives: Cell–cell communication (CCC) is a critical process within the tumor microenvironment, governing regulatory interactions between cancer cells and other cellular subpopulations. Aiming to improve the accuracy and completeness of intercellular gene-regulatory network inference, we constructed a novel spatial-resolved gene-regulatory network framework (spGRN). Methods: Firstly, the spatial multi-omics data of colorectal cancer (CRC) patients were analyzed. We precisely located the tumor boundaries and then systematically constructed the spGRN framework to study the network regulation. Subsequently, the key signaling molecules obtained by the spGRN were identified and further validated by the spatial-proteomics dataset. Results: Through the constructed spatial gene regulatory network, we found that in the communication with malignant cells, the highly expressed ligands LIF and LGALS3BP and receptors IL6ST and ITGB1 in fibroblasts can promote tumor proliferation, and the highly expressed ligands S100A8/S100A9 in plasma cells play an important role in regulating inflammatory responses. Further, validation of the key signaling molecules by the spatial-proteomics dataset highlighted the role of these genes in mediating the regulation of boundary-related cells. Furthermore, we applied the spGRN to publicly available single-cell and spatial-transcriptomics datasets from three other cancer types. The results demonstrate that ITGB1 and its target genes FOS/JUN were commonly expressed in all four cancer types, indicating their potential as pan-cancer therapeutic targets. Conclusion: the spGRN was proven to be a useful tool to select signal molecules as potential biomarkers or valuable therapeutic targets. Full article
(This article belongs to the Special Issue Single-Cell and Spatial Multi-Omics in Human Diseases)
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25 pages, 7641 KiB  
Article
Integrated Single-Cell Analysis Dissects Regulatory Mechanisms Underlying Tumor-Associated Macrophage Plasticity in Hepatocellular Carcinoma
by Yu Gu, Wenyong Zhu, Zhihui Zhang, Huiling Shu, Hao Huang and Xiao Sun
Genes 2025, 16(7), 817; https://doi.org/10.3390/genes16070817 - 12 Jul 2025
Viewed by 694
Abstract
Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes [...] Read more.
Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes at high resolution. By correlating chromatin accessibility with gene expression, we identified cell-type-specific candidate cis-regulatory elements (CREs). TAM subsets with prognostic significance were determined through integration with HCC clinical cohorts. Pseudotime and multi-regional analyses were used to uncover regulatory trajectories underlying macrophage phenotypic transitions. The identification framework of a super-enhancer (SE) was constructed, and potential therapeutic targets were prioritized using drug–gene interaction data. Results: We delineated the regulatory landscape of TAMs in HCC, revealing cell-type-specific chromatin accessibility patterns underlying TAM heterogeneity. The 65,342 CREs linked to gene expression were identified, with distal CREs contributing most to cell-type-specific regulation. Notably, SPP1+ TAMs were found to be enriched in tumor cores and associated with poor prognosis in HCC. Liver-resident Kupffer cells showed progressive loss of the core transcription factors SPIC and MAFB, suggesting a potential transition into SPP1+ TAMs under tumor pressure. We identified 133 SPP1+ TAM-specific SEs and constructed a TF–SE–target gene regulatory network. Notably, 13 target genes showed higher drug–gene interaction effects, highlighting their therapeutic potential. Conclusions: This study provides the chromatin accessibility map of TAMs in HCC and reveals how distal CRE-driven transcriptional programs shape TAM states. Our findings lay the foundation for understanding the epigenetic regulation of TAM heterogeneity and nominate potential targets for TAM-directed immunotherapy in HCC. Full article
(This article belongs to the Special Issue Single-Cell and Spatial Multi-Omics in Human Diseases)
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