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Open research questions in Single-cell and spatial transcriptomics

602 unresolved questions extracted from the limitations and future-work sections of 1,353 Single-cell and spatial transcriptomics papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • In our double-gene OOD setting, generic compression followed by additive extrapolation remains insufficient to match PerturbedVAE, supporting the need for perturbation-aware modeling beyond standard low-dimensional representation extraction.

    What Makes a Representation Good for Single-Cell Perturbation Prediction? · 2026

  • Direct causal evidence linking variation within individual CNEs to human-specific brain phenotypes is still limited, - Conservation alone does not establish regulatory function, and many CNEs remain uncharacterized in relevant neural cell types and developmental stages, - Challenges remain in establishing causal relationships between regulatory variation and phenotypic outcomes

    Regulatory Evolution and the Genetic Basis of Human Brain Expansion · 2026 · DOI

  • The paper identifies a gap in understanding how regulatory evolution contributes to human-specific brain phenotypes. It highlights the need for direct causal evidence linking variation within individual conserved noncoding elements to human-specific brain phenotypes. The paper also notes the challenge in establishing causal relationships between regulatory variation and phenotypic outcomes.

    Regulatory Evolution and the Genetic Basis of Human Brain Expansion · 2026 · DOI

  • technological limitations associated with single-cell and spatial omics assays - lack of standardized protocols and procedures - limitations in identifying stress-associated changes in protein-protein dynamics and protein functions

    Single-Cell and Spatial Omics in Plant Defense: Developments and Prospects · 2026 · DOI

  • Integration of single-cell and spatial omics data - Development of robust computational frameworks - Application of single-cell and spatial omics for crop improvement under stressful environmental conditions

    Single-Cell and Spatial Omics in Plant Defense: Developments and Prospects · 2026 · DOI

  • The uterus comprises diverse cell populations that exhibit substantial cellular and transcriptional heterogeneity. Conventional bulk RNA-seq cannot resolve cell-type-specific expression patterns and intercellular interactions. There is a lack of understanding of the cellular composition and molecular features of the rabbit uterus.

    Single-Cell RNA Sequencing of Uterine Tissue from a 70-Day-Old Female Rabbit: Cellular Composition and Fibroblast-Associated Networks · 2026 · DOI

  • High inter-rater variability in manual gating. High dimensionality of flow cytometry data, with up to 30 markers. Limited consistency across studies due to increasing numbers of measured parameters. Technical challenges in sorting cells from tissues with high lipid content and cellular fragility, such as visceral white adipose tissue.

    ConvexGating infers gating strategies from clusters in single cell cytometry data · 2026 · DOI

  • leveraging large-scale panels as created with CITE-seq, - demonstrating the applicability of ConvexGating to high-dimensional mass cytometry data, - examining ways to leverage ConvexGating for cell sorting beyond immune cells

    ConvexGating infers gating strategies from clusters in single cell cytometry data · 2026 · DOI

  • Limited cell-level labels and annotations. Technical challenges in linking single-cell transcriptomic profiles with sample-level labels. The presence of normal cells in tumor samples that obscure signals and make CNV-based discrimination challenging.

    scTransMIL bridges patient-level disease states and single-cell transcriptomics for cancer screening and heterogeneity inference · 2026 · DOI

  • limited cell-level labels, - the presence of normal cells in tumor samples that obscure CNV signals, - CNV-based discrimination is particularly challenging when CNV signals are subtle, - the model relies solely on bag labels for supervised learning

    scTransMIL bridges patient-level disease states and single-cell transcriptomics for cancer screening and heterogeneity inference · 2026 · DOI

  • Conventional single-cell technologies often fail to retain critical spatial information. The need for a comprehensive understanding of protein organization at the nanoscale level. The challenge of achieving single-cell resolution in spatial omics technologies.

    Spatial Omics in Clinical Research: A Comprehensive Review of Technologies and Guidelines for Applications · 2025 · DOI

  • Technical batch effects in traditional scRNA-seq protocols. Limited sample-level throughput in traditional scRNA-seq protocols. Background noise in the library affecting scRNA-seq efficiency.

    Comparative Analysis of Single-Cell RNA Sequencing Methods with and without Sample Multiplexing · 2024 · DOI

  • future studies should include samples from multiple developmental and physiological stages, - systematically characterize changes in cellular composition from uterine development and maturation to pregnancy, - analyze the single-cell transcriptome from multiple biological specimens

    Single-Cell RNA Sequencing of Uterine Tissue from a 70-Day-Old Female Rabbit: Cellular Composition and Fibroblast-Associated Networks · 2026 · DOI

  • Single-nucleus RNA sequencing (snRNA-seq) bypasses several of these challenges, but its performance in lung disease models is not well characterized.

    Dynamics of bleomycin-induced lung injury at single-nucleus resolution · 2026 · DOI

  • However, its conventional zero-threshold rule does not account for sampling uncertainty in the fitted score difference and may therefore favor overly complex models in finite samples.

    Uncertainty-Aware Model Selection with a Calibrated Probability-Generating-Function-Based Bayesian Information Criterion · 2026 · DOI

  • Early-life environment and parental background can shape immune phenotypes, but whether such differences persist during infection and influence the immune response remains unclear.

    Early-life conditions shape baseline immune gene expression, but not pathogen-induced immune activation, in brown trout · 2026 · DOI

  • Multi-step cell state transitions occur across biological processes, such as development and disease progression, yet the underlying gene regulation remains unclear.

    Building dynamical models of multi-step state transitions from single cell gene expression trajectories · 2026 · DOI

  • However, most studies have focused on malignant cells, and the spatial and cellular heterogeneity of the tumor microenvironment (TME) remains poorly understood.

    Local Tumor Microenvironment Niches Correlate with Survival and Immunotherapy Response in Human Glioblastoma · 2026 · DOI

  • Whilst previous studies have characterized diverse features related to the neurochemical substrate of serotonergic neurotransmission and behavioral presentation between males and females, no investigations have fully addressed the sexual dimorphism in the structural and functional connectivity of serotonergic circuits.

    Serotonergic circuit architecture underlies sex dimorphism in anxiogenic states · 2026 · DOI

  • Neoadjuvant immunotherapy has transformed cancer treatment, yet the spatial molecular architecture governing response and resistance across distinct immune checkpoint blockade (ICB) regimens remains poorly defined.

    Spatially resolved multimodal hallmarks of response to neoadjuvant immunotherapies in the melanoma ecosystem in 2D and 3D · 2026 · DOI

  • Abstract Aims The cardiovascular system is tightly regulated by the nervous system, yet while cardiac nexus glial cells are known modulators of physiology, the identity and functional significance of glial populations within the vasculature remain poorly defined.

    Vascular nexus glia regulates vascular homeostasis and undergoes dynamic remodelling in deep vein thrombosis · 2026 · DOI

  • However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here.

    Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra -lineage-positive cells and predominantly maintain fibroblast identity · 2026 · DOI

  • Background: Accurate prediction of the progression of brucellosis is critical for optimizing therapeutic interventions, yet reliable biomarkers for this transition remain elusive.

    Single-Cell Transcriptomic Profiling and Machine Learning Reveal Stage-Specific Gene Dynamics in Brucellosis · 2026 · DOI

  • Lack of data-driven analytical frameworks remains a significant barrier to reproducible and biologically robust analyses.

    A single-cell atlas and Shiny-based framework for murine lung injury and remodeling · 2026 · DOI

  • Macrophages are key contributors to DKD pathogenesis, yet their functional heterogeneity in the diabetic kidney remains poorly defined.

    Spatially Distinct TREM2+ Macrophages Are Associated with Compartment-Specific Protection in Diabetic Kidney Disease · 2026 · DOI

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602 open questions have been extracted from the limitations and future-work passages of 1,353 Single-cell and spatial transcriptomics papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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