Single-Cell and Spatially Resolved Transcriptomics: Charting Cellular Landscapes in Health and Disease

Introduction

The past five years have witnessed an explosion in the application of single-cell and spatially resolved transcriptomics, revolutionizing our understanding of cellular heterogeneity and organization across various tissues and organisms. This mini-review highlights recent advancements in the field, focusing on the construction of comprehensive cell atlases and the application of these atlases to study disease and development.

Single-Cell Atlas Construction: Defining Cellular Diversity

A major focus has been the creation of single-cell transcriptomic atlases across diverse species and tissues. These atlases provide a foundational resource for understanding cellular identity, function, and interactions.

• Human Cell Atlases: Several large-scale projects have aimed to map the human body at single-cell resolution. Tony Wyss-Coray's group contributed significantly to the Tabula Sapiens, a multiple-organ, single-cell transcriptomic atlas of humans, with publications spanning from 2020 to 2022 (The Tabula Sapiens Consortium et al., 2020, Science; The Tabula Sapiens Consortium et al., 2021, Science; The Tabula Sapiens Consortium et al., 2022, Science). Other human atlases include those focusing on specific tissues, such as the endometrium (Stephen R. Quake's group, Wanxin Wang et al., 2020, Nature Medicine), the fetal lung (Emma L. Rawlins's group, Peng He et al., 2022, Cell), the myometrium (Nardhy Gomez‐Lopez's group, Roger Piqué-Regi et al., 2022, JCI Insight), the tonsil (Ramon Massoni-Badosa's group, Ramon Massoni-Badosa et al., 2024, Immunity), and the bone marrow (Kai Tan's group, Shovik Bandyopadhyay et al., 2024, Cell). These atlases are invaluable for understanding tissue-specific cellular composition and function.
• Model Organism Atlases: In parallel with human atlas efforts, researchers have also generated single-cell atlases for model organisms. Sten Linnarsson's group created an atlas of the developing mouse brain (Gioele La Manno et al., 2020, Nature; Gioele La Manno et al., 2021, Nature). Robert P. Zinzen's group constructed a single-nucleus transcriptomic atlas of the adult fruit fly (Hongjie Li et al., 2022, Science). Uwe Ohler's group focused on the Arabidopsis root (Rachel Shahan et al., 2020, Developmental Cell; Rachel Shahan et al., 2021, Developmental Cell; Rachel Shahan et al., 2022, Developmental Cell). These atlases provide insights into developmental processes and cellular function in well-characterized genetic systems.
• Plant Cell Atlases: Single-cell transcriptomics has also been applied to plant biology. Ji Yun Kim's group investigated leaf phloem cells (Ji Yun Kim et al., 2020, The Plant Cell; Ji Yun Kim et al., 2021, The Plant Cell). Qing Huan's group generated an atlas of the leaf and root of rice seedlings (Yu Wang et al., 2020, Journal of genetics and genomics/Journal of Genetics and Genomics; Yu Wang et al., 2021, Journal of genetics and genomics/Journal of Genetics and Genomics). Chuankui Song's group studied tea leaves (Qiang Wang et al., 2022, Plant Biotechnology Journal). Xianlong Zhang's group studied developing cotton anthers (Yanlong Li et al., 2023, Advanced Science). Zhe Yan's group studied soybean nodule maturation (Zhijian Liu et al., 2023, Nature Plants). These studies provide insights into plant development, metabolism, and responses to environmental stimuli.

Spatial Transcriptomics: Mapping Cellular Organization

While single-cell transcriptomics provides information about cellular identity, spatial transcriptomics adds another layer of complexity by mapping the location of cells within tissues.

• Spatial Mapping in the Brain: Xiaowei Zhuang's group has been at the forefront of spatial transcriptomics, using MERFISH to create spatially resolved cell atlases of the mouse primary motor cortex (Meng Zhang et al., 2020, Nature; Meng Zhang et al., 2021, Nature) and the whole mouse brain (Meng Zhang et al., 2022, Nature; Meng Zhang et al., 2023, Nature). Hongkui Zeng's group also contributed a high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (Zizhen Yao et al., 2022, Nature; Zizhen Yao et al., 2023, Nature). Xiao Wang's group created a spatial atlas of the mouse central nervous system at molecular resolution (Hailing Shi et al., 2023, Nature). These studies reveal the intricate organization of the brain and how it changes during development and aging.
• Spatial Mapping in Other Tissues: Spatial transcriptomics is also being applied to study other tissues, including the human breast (Alexander Swarbrick's group, Sunny Z. Wu et al., 2021, Nature Genetics; Nicholas Navin's group, Tapsi Kumar et al., 2023, Nature), the liver (Charlotte L. Scott's group, Martin Guilliams et al., 2021, Cell; Martin Guilliams et al., 2022, Cell; Tallulah Andrews's group, Tallulah Andrews et al., 2024, Journal of Hepatology), and the kidney (Benjamin D. Humphreys's group, Haikuo Li et al., 2024, Cell Metabolism). These studies provide insights into the cellular microenvironment and how it influences tissue function and disease.

Applications to Disease and Development

Single-cell and spatial transcriptomics are powerful tools for studying disease and development.

• Cancer Biology: Several studies have used these technologies to characterize the tumor microenvironment and identify potential therapeutic targets. Jane E. Visvader's group created a single-cell RNA expression atlas of normal, preneoplastic, and tumorigenic states in the human breast (Bhupinder Pal et al., 2020, The EMBO Journal; Bhupinder Pal et al., 2021, The EMBO Journal). Xiaoming Zhang's group investigated the spatiotemporal immune landscape of colorectal cancer liver metastasis (Yingcheng Wu et al., 2020, Cancer Discovery; Yingcheng Wu et al., 2021, Cancer Discovery). Fei Wang's group performed single-cell and spatial transcriptome analysis of liver metastatic colorectal cancer (Fei Wang et al., 2023, Science Advances). Junjun Qiu's group studied cervical squamous carcinoma (Junjun Qiu et al., 2023, Advanced Science). Zhijia Xia's group investigated T-cell exhaustion signatures in hepatocellular carcinoma (Hao Chi et al., 2023, Front. immunol.). Jong-Eun Park's group systematically dissected tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types (Junho Kang et al., 2024, Nature Communications). Yi Zhang's group studied intratumoral heterogeneity in human bladder urothelial carcinoma (Yu Xiao et al., 2024, Advanced Science). Weijuan Zhang's group identified a better response subset to immunotherapy in muscle-invasive bladder cancer (Ge Liu et al., 2024, Cancer Medicine). Chuzhong Li's group analyzed pituitary neuroendocrine tumors (Nan Yan et al., 2024, Genome med.).
• Immunology: Single-cell transcriptomics has also been used to study immune responses in various contexts. Zhiwei Huang's group investigated COVID-19 immune features (Xianwen Ren et al., 2020, Cell; Xianwen Ren et al., 2021, Cell). Yi Wang's group compared immunological responses between COVID-19 vaccine and natural SARS-CoV-2 infection (Yi Wang et al., 2022, Journal of Medical Virology). Paige M. Porrett's group studied the spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant (Matthew D. Cheung et al., 2024, Nature Communications). Christophe Benoist's group studied immunocyte migration from the gut (Silvia Galván-Peña et al., 2024, Science Immunology).
• Neurodegenerative Diseases: Tony Wyss-Coray's group has used single-cell transcriptomics to study Alzheimer's disease, creating a human brain vascular atlas (Andrew C. Yang et al., 2021, Nature; Andrew C. Yang et al., 2022, Nature) and an atlas of the aging mouse brain (Oliver Hãhn et al., 2023, Cell). Tomasz J. Nowakowski's group created a single-cell atlas of the normal and malformed human brain vasculature (Ethan A. Winkler et al., 2022, Science).

Conclusion

Single-cell and spatially resolved transcriptomics have rapidly advanced in the past five years, providing unprecedented insights into cellular heterogeneity and organization. The creation of comprehensive cell atlases, coupled with the application of these atlases to study disease and development, has revolutionized our understanding of biology. Future research will likely focus on integrating multi-omics data, developing more sophisticated analytical tools, and applying these technologies to a wider range of biological questions.