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Single-cell analysis of the tumor microenvironment landscape across the disease spectrum of multiple myeloma.
Multiple myeloma (MM) progresses from precursor states to active disease, and studying tumor microenvironment (TME) evolution across these stages is key to understanding immune dysregulation and therapeutic resistance. Here, we integrated paired single-cell RNA and T- and B-cell receptor sequencing data from bone marrow (BM) samples of 235 patients spanning the disease spectrum. This data set revealed dynamic changes in the abundance and functional states of diverse immune populations, including T, natural killer, B, and myeloid cells. Using nonnegative factorization of cell-subset composition, we identified 5 reproducible TME subtypes, or "ecotypes," defined by coordinated cellular architectures. These ecotypes captured structured variation beyond disease stage and were associated with distinct cell-cell communication networks, cytokine signaling landscapes, transcription factor programs, and shared gene modules, reflecting a coordinated immune adaptation to microenvironmental constraints. By linking tumor features with immune changes and ecotype distributions, we identified context-dependent associations influenced by both disease biology and treatment effects on the TME. We found that an ecotype enriched for BM-resident populations and limited immune infiltration was associated with tumor expansion and inferior clinical outcomes, whereas ecotypes reflecting T-cell functional states showed distinct associations with immunotherapy response and survival. Our study provides a comprehensive single-cell immune atlas of MM and its precursors, offering insights into TME organization and progression, and may guide the development of stage-specific or ecotype-targeted immunotherapies.
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Single-nucleus atlas of cell-type specific genetic regulation in the human brain.
Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. Here we present a comprehensive, single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6 million nuclei from 1,384 donors of diverse ancestries. Through multi-resolution analyses spanning eight major cell classes and 27 subclasses, we identify genetic regulation for 14,258 genes, with 981 showing cell type-specific regulatory effects at the class level and 857 at the subclass level. Colocalization of genetic variants associated with gene regulation and disease traits uncovers novel cell type-specific genes implicated in Alzheimer's disease, schizophrenia and other disorders that were not detectable in bulk tissue analyses. Analysis of dynamic genetic regulation at the single-nucleus level identifies 2,073 genes with regulatory effects that vary across developmental trajectories, inferred from a broad age range of donors. We also uncover 1,655 genes with trans-regulatory effects, revealing distal regulation of gene expression. This high-resolution atlas provides insight into the cell type-specific regulatory architecture of the human brain, and offers novel mechanistic targets for understanding the genetic basis of neuropsychiatric and neurodegenerative diseases.
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Peripheral γδ T-cell remodeling in psoriasis is associated with effector-biased transcriptional organization and reduced representation of a circulating CSMD1-marked state.
BACKGROUND: Despite the prominent immune dysregulation in psoriasis, the organization of peripheral blood γδ T cell states remains incompletely defined. METHODS: Here, we performed single-cell transcriptomic profiling of enriched peripheral blood-derived γδ T cells from healthy donors and patients with psoriasis. By integrating state annotation, inferred transcriptional ordering, ligand-receptor communication, transcriptome-inferred metabolite-sensor communication, and regulatory network analyses, we constructed a circulating γδ T-cell state atlas. RESULTS: We identified eight γδ T-cell states. Within the resolution of this dataset, psoriasis-derived cells did not form a clearly separated disease-exclusive state; instead, disease-associated changes were mainly reflected by altered representation and transcriptional organization of pre-existing states, including reduced peripheral representation of a CSMD1-marked γδ T-cell state. Pseudotime analysis arranged γδ T cells along an inferred activation- and cytotoxicity-associated transcriptional continuum, with Naive-like cells at the lower-pseudotime region and cytotoxic effector-, NK-like-, cytotoxic memory-like-, terminal-branch-, and CSMD1-marked states toward higher-pseudotime regions. Psoriasis-derived γδ T cells were more frequent in cytotoxicity-related regions. This pattern suggests a shift toward effector states. In parallel, peripheral γδ T cell communication suggested cytotoxic-state-biased ligand-receptor patterns, with rewiring of MIF-related and metabolic signaling and reduced network participation of CSMD1 + γδ T cells. Regulatory analyses further linked FOXP1, STAT1, and NFATC3 as candidate regulators associated with early-like, transitional/CSMD1-marked, and cytotoxic-associated transcriptional states, respectively. CONCLUSIONS: These findings support a state-resolved framework of circulating γδ T-cell remodeling in psoriasis and identify reduction and possible redistribution of a CSMD1-marked late-stage state as a feature of disease-associated immune remodeling.
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Identification of human cranio-maxillofacial skeletal stem cells for mandibular development.
Compared with long bone that arises from the mesoderm, the major portion of the maxillofacial bones and the front bone of the skull are derived from cranial neural crest cells and undergo intramembranous ossification. Human skeletal stem cells have been identified in embryonic and fetal long bones. Here, we describe a single-cell atlas of the human embryonic mandible and identify a population of cranio-maxillofacial skeletal stem cells (CMSSCs). These CMSSCs are marked by interferon-induced transmembrane protein 5 (IFITM5) and are specifically located around the periosteum of the jawbone and frontal bone. Additionally, these CMSSCs exhibit strong self-renewal and osteogenic differentiation capacities but lower chondrogenic differentiation potency, mediating intramembranous bone formation without cartilage formation. IFITM5+ cells are also observed in the adult jawbone and exhibit functions similar to those of embryonic CMSSCs. Thus, this study identifies CMSSCs that orchestrate the intramembranous ossification of cranio-maxillofacial bones, providing a deeper understanding of cranio-maxillofacial skeletal development and promising seed cells for bone repair.
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Vascular smooth muscle cell state trajectories mediate molecular mechanisms of coronary disease risk.
Vascular smooth muscle cells contribute to heritable coronary artery disease risk and undergo complex transitions to multiple disease-related phenotypes. To investigate the genetic basis of these trajectories, we develop a dense timecourse single-cell transcriptomic and epigenetic map of atherosclerosis in a murine disease model accompanied by high-plex in situ spatial data. Using temporal data and probabilistic fate modeling, we identify key transcription factors that drive cell state changes through a combination of network-based prioritization and in silico transcription factor perturbation. Parallel knockout studies of validated coronary artery disease gene Tcf21 uncover its molecular mechanisms in smooth muscle cell transition, due in part to a role regulating the transition of smooth muscle cells in the secondary heart field. Integrating the murine atlas with human coronary artery disease genetics pinpoint smooth muscle cell phenotypes that mediate disease risk, highlighting causal disease mechanisms. Together, these studies resolve atherosclerosis trajectories at single-cell resolution and identify genetic causal transcriptomic and epigenomic mechanisms of coronary artery disease risk.
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A transcriptomic microglia taxonomy across mouse and human pathologies.
Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.
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Life-span-dependent transcriptional dynamics of the human heart.
The human heart undergoes continuous transcriptional remodeling from development through aging, yet the cellular and regulatory features governing this process remain incompletely defined. Here, we generated a single-nucleus RNA sequencing atlas of 442,239 nuclei from 54 nonfailing myocardial tissues of 29 individuals spanning development, adulthood, and aging, covering left and right ventricles. Across all major cell types, we uncovered coordinated yet cell type-specific transcriptional trajectories that converge on progressive loss of gene expression homeostasis, stress responses, and inflammatory signaling over the life span. Cardiomyocytes displayed distinct age-associated transcriptional states enriched for senescence- and disease-related signatures. Regulatory network analysis identified PRDM16 as a transcriptional regulator whose activity declined with age in cardiomyocytes. Functional perturbation of PRDM16 in human cardiomyocyte models induced senescence, metabolic dysfunction, and stress responses, whereas its rebalancing in aged mouse hearts improved cardiac function and partially reversed aging-associated transcriptional programs. Last, leveraging life-span-resolved single-nucleus data, we constructed cardiac transcriptomic age prediction models that closely tracked chronological age in nonfailing hearts and revealed deviations consistent with accelerated aging in cardiomyopathies. Together, this study provides a comprehensive single-nucleus resource of the human heart across the life span and delineates cellular and regulatory features associated with cardiac aging.
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Single-cell atlas of transcriptomic vulnerability across brain disorders.
Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited1,2. Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual nuclei. The cohort includes neurotypical controls, as well as donors affected by eight common and complex brain disorders: Alzheimer's disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson's disease (PD), tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder. We show that interindividual variation accounts for a substantial portion of gene expression variation. By comparing transcriptomic variation across diseases, we reveal universal signatures enriched in basic cellular functions such as mRNA processing and protein localization. After discounting these cross-disease signatures, we show stronger genetic and transcriptomic concordance among AD, DLBD, Vas and PD. Furthermore, we characterize transcriptomic variation among different AD phenotypes, distinct from those observed in healthy ageing, revealing a reduction in neuronal abundance in individuals with more severe AD, coupled with an increase in immune and vascular cell populations. Exploring the neuropsychiatric symptoms (NPSs) that frequently accompany AD, we find an increased abundance of deep-layer excitatory neurons associated with a broad range of NPSs. By constructing transcriptome trajectories that capture AD progression, we implicate cell-type-specific responses in the early and late stages of AD. Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological-immune-vascular systems, and identifying potential targets for therapeutic intervention.
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Single-nucleus transcriptome-wide association study of human brain disorders.
Common brain disorders impose a substantial health burden, but localizing their genetic risk in the brain remains challenging1. Although genome-wide association studies have identified numerous loci associated with neuropsychiatric and neurodegenerative disorders, many of these loci lie in non-coding regions that influence gene expression in specific cell types2-5. Traditional bulk brain transcriptomic analyses, which often focus on European ancestry cohorts, average over cellular diversity, obscuring genetic risk-related changes in gene expression. Here we use single-nucleus gene expression profiles from the dorsolateral prefrontal cortex in the multi-ancestry PsychAD cohort to develop transcriptomic imputation models of genetically regulated expression across major brain cell types. Applying these models to neuropsychiatric and neurodegenerative disorders reveals thousands of gene-trait associations that are undetectable in bulk tissue analyses and resolves many signals to discrete neuronal, glial and immune cell populations. Cross-ancestry analyses in the Million Veteran Program confirm these associations, reveal pleiotropic effects of cell-type-specific predicted expression and demonstrate that trait-related dysregulation is conserved across ancestries, enabling mapping of causal genes and pathways. Together, these findings provide a cell-type-resolved and ancestry-aware atlas of genetically regulated expression in the human prefrontal cortex and illustrate how single-nucleus transcriptomics can sharpen gene discovery and therapeutic target prioritization for complex brain disorders.
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Early Alzheimer's disease pathology in human cortex involves transient cell states.
Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.