Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH
Open accessAbstract
Imaging the transcriptome in situ with high accuracy has been a major challenge in single-cell biology, which is particularly hindered by the limits of optical resolution and the density of transcripts in single cells 1-5. Here we demonstrate an evolution of sequential fluorescence in situ hybridization (seqFISH+). We show that seqFISH+ can image mRNAs for 10,000 genes in single cells-with high accuracy and sub-diffraction-limit resolution-in the cortex, subventricular zone and olfactory bulb of mouse brain, using a standard confocal microscope. The transcriptome-level profiling of seqFISH+ allows unbiased identification of cell classes and their spatial organization in tissues. In addition, seqFISH+ reveals subcellular mRNA localization patterns in cells and ligand-receptor pairs across neighbouring cells. This technology demonstrates the ability to generate spatial cell atlases and to perform discovery-driven studies of biological processes in situ.
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The lack of single-cell resolution with ST and the low sensitivity of ISS requires further technological improvements.
“While the technologies used here do not require harsh dissociation procedures like single-cell or single-nuclei approaches and maintain spatial information, the lack of single-cell resolution with ST and the low sensitivity of ISS requires further technological improvements (Eng et al. , 2019; Rodriques et al. , 2019; Vickovic et al. , 2019; Stickels et al. , 2020).”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Eng et al., 2019
These methods detect up to 3,300 genes per cell in mouse brain, ~3-fold less than highest-resolution sc/snRNA-seq.
“These methods detect up to 3,300 genes per cell in mouse brain (Eng et al., 2019), ~3-fold less than the highest-resolution sc/snRNA-seq (Yao et al., 2020a).”
From Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes (2021) · cites this paper as Eng et al., 2019
seqFISH+ can image mRNAs for 10,000 genes in single cells.
“Sequential FISH (seqFISH+) demonstrated the ability to perform discovery-driven studies of the spatial organization of tissues with its capability of imaging mRNAs for 10,000 genes in single cells102.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [102]
Multiplex fluorescence in situ hybridization (mFISH) can detect more than 100 selected genes at single-molecule resolution.
“Multiplex fluorescence in situ hybridization (mFISH) [34,35] is another effective approach to detect senescent cells, which can detect more than 100 selected genes at single-molecule resolution.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [34]
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- Authors
- Eng, C.-H. L., Lawson, M., Zhu, Q., Dries, R., Koulena, N., Takei, Y., Yun, J., Cronin, C., Karp, C., Yuan, G.-C., & Cai, L.
- Affiliations
- California Institute of Technology (US)
- Harvard University (US)
- Corresponding author
- Cai, Long
- ORCID
- Venue
- Nature
- Published
- 2019-03-25
- Volume
- 568
- Issue
- 7751
- Pages
- 235-239
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6544023
- OpenAlex
- W2923300855
- Cited by
- 1,754
- References
- 41
- Citations by year
- 2026: 257 · 2025: 240 · 2024: 283 · 2023: 235 · 2022: 217 · 2021: 270 · 2020: 181 · 2019: 68 · 2017: 2
- FWCI
- 61.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (TR01 OD024686)
- National Heart, Lung, and Blood Institute (UG3HL145609, U54HL145611)
- National Institute of Mental Health (R01MH116508)
- National Institute on Drug Abuse (U01DA047732)
- National Institute of Neurological Disorders and Stroke (U19NS107613)
- National Institute of Biomedical Imaging and Bioengineering (U01EB021240)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
- Keywords
- seqFISH, super-resolution imaging, single-cell transcriptomics, mRNA localization, subcellular mRNA localization, ligand-receptor interactions, subventricular zone, olfactory bulb, confocal microscopy
- MeSH terms
- Animals, Brain, Female, Ligands, Male, Organ Specificity, RNA, Messenger, 3T3 Cells, In Situ Hybridization, Fluorescence, Microglia, Gene Expression Profiling, Endothelial Cells, Mice, Single-Cell Analysis, Dopaminergic Neurons, Transcriptome
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