Cell Discovery最新文献

Deciphering the spatial organization of cell states is fundamental for understanding development, tissue homeostasis and disease. Emerging advances in spatial transcriptomic profiling techniques allow transcript localization but face limitations in unambiguous cell state assignments due to cellular boundary inference, low gene detection and prohibitive cost. Here, a method, Stamp-seq, is developed that leverages custom-fabricated high-density DNA sequencing chips to label single nuclei with restriction enzyme-cleavable spatial barcodes. Stamp-seq spatial barcodes are distributed at a density of 1.6 μm on the chip, allowing for single physical cell resolution with precise subtype classification and spatial mapping (with an average 4 μm localization error) and reduced cost. We utilize Stamp-seq to delineate chemoimmunotherapy-responsive cellular ecosystems in non-small cell lung carcinoma, including a distinct IGHG1⁺ plasma cell-enriched community. Through a novel application of Stamp-seq to spatially resolve BCR clonotypes, we elucidate the spatiotemporal trajectory of treatment-potentiating IGHG1⁺ plasma cells, which originate from tertiary lymphoid structures (TLSs) or the vasculature, migrate through antigen-presenting CAF (apCAF)-enriched survival niches, and ultimately contact tumor cells. We highlight the power of spatial cellular subtyping and molecular tracking using Stamp-seq and suggest that the IGHG1⁺ plasma cell niche is a better prognostic biomarker for the chemoimmunotherapy response.

Deeper insights into omics in the clinical and tumor microenvironments of lung adenocarcinoma (LUAD) could reveal therapy-sensitive subtypes and novel treatments. From a cohort of 1008 samples from Chinese patients with LUAD with whole-genome and transcriptome sequencing data along with comprehensive longitudinal clinical and therapeutic information, we identified four prognostically distinct subtypes, namely, low proliferation and invasion (LPI), immune-desert (IMD), immune-enriched (IME), and high proliferation and invasion (HPI), based on the transcriptomic features linked to the radiological, pathological, and microenvironmental dimensions. Compared with chemotherapy, tyrosine kinase inhibitor (TKI) therapy demonstrated significantly superior efficacy for LPI and IMD, whereas no such difference was observed for HPI. VOPP1 and RRM2B amplification were closely associated with TKI resistance and sensitivity, respectively. VOPP1 knockdown restored sensitivity to TKI treatment, while RRM2B knockdown induced TKI resistance, and its overexpression restored sensitivity. Patients with RRM2B amplification had a 5-year survival rate of nearly 100%. Additionally, the IME subtype exhibited higher immune checkpoint activity and a higher frequency of DYNC2H1 mutation, with patients benefiting from immunotherapy. These findings provide critical insights into LUAD treatment optimization.

Aging impairs the regenerative capacity and differentiation potential of human adipose-derived stem cells (hASCs), but the mechanisms underlying their functional decline remain unclear. Through systematic functional assays and in vivo experiments, we first confirmed age-associated reductions in hASC self-renewal, lineage plasticity, and tissue repair efficacy. By integrating multiomics profiling and functional validation, we identified a metabolically active ACTA2⁺TAGLN⁺ subpopulation that was enriched mainly in infant-derived hASCs (I-hASCs) and characterized by increased catabolism of branched-chain amino acids (BCAAs) and glutamine. Mechanistically, the RNA-binding protein IGF2BP3, which is predominantly expressed in the ACTA2⁺TAGLN⁺ subpopulation, sustains hASC stemness by stabilizing BCAT1 and GLS mRNAs via METTL3-mediated m6A modification, thereby preserving redox homeostasis and mitochondrial energy production. Furthermore, age-related attenuation of the IGF2BP3-m6A-BCAT1/GLS axis contributed to metabolic reprogramming, driving senescence-associated functional collapse in elderly-derived hASCs (E-hASCs). Strikingly, rescue experiments demonstrated that genetic restoration of BCAT1/GLS or supplementation with BCAAs/glutamine significantly rejuvenated E-hASCs, restoring their proliferation, differentiation, and in vivo wound-healing capacities. These findings identify IGF2BP3 as a central regulator of hASC aging by linking m6A epitranscriptomic modifications to metabolic reprogramming and establish the IGF2BP3-m6A-BCAT1/GLS axis as a druggable node in aged hASCs. This study proposed two therapeutic strategies: nutrient supplementation to rescue metabolic deficits and m6A modulation to stabilize key mRNAs, providing a clinically feasible protocol to optimize elderly-derived hASCs for tissue regeneration.

Osteoclasts are bone-resorbing cells that play a central role in normal bone remodeling and contribute to bone loss associated with pathological conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, periodontal disease, and bone metastases of cancer. The commitment, differentiation, and function of osteoclasts depend on the establishment of specific gene expression patterns orchestrated through a network of transcription factors, which are sequentially activated by osteoclastogenic signals. This review provides an updated overview of the roles of key signaling pathways (e.g., RANKL signaling, NF-κB signaling and Gα₁₃ signaling), transcription factors (e.g., PU.1, C/EBP-α, NFATc1 and IRF8), cytokines (e.g., TNF-α, IL-1β and IL-6), and epigenetic regulators (e.g., DNMT3a, EZH2 and ASXL1) in osteoclast lineage commitment, differentiation and bone resorption under both physiological and pathological inflammatory conditions, along with insights from corresponding mouse models. We described the mechanism by which osteoclast-mediated bone resorption occurs through extracellular acidification driven by osteoclast-specific proton pump subunits (e.g., ATP6i and ATP6v0d2), followed by matrix protein degradation mediated by cathepsin K and MMP-9. Additionally, this review examines the interplay among molecular mechanisms that regulate osteoclast differentiation and activation under pathological and inflammatory conditions, elucidates their roles in osteoclast hyperactivation-related human diseases, and provides a comprehensive framework for understanding these processes. Finally, it underscores potential novel therapeutic strategies for osteoclast-related skeletal lytic diseases and highlights perspectives for future investigations.

Mammalian wound healing is orchestrated by tightly regulated cellular and molecular programs across the hemostasis, inflammation, proliferation, and remodeling phases. Here, we propose the concept of spatiotemporal clocks as a unifying framework for understanding how transitions between phases are coordinated. We dissect the roles of distinct spatial domains: epidermis, dermis, fascia, wound edges, and wound center, and highlight the oscillatory molecular signals that govern their dynamic interactions. Special attention is given to wound-induced hair neogenesis (WIHN) as a model of regenerative potential. By integrating spatial and temporal dimensions, this framework unifies the multidimensional aspects of wound healing, laying a robust foundation for the development of innovative therapeutic strategies.

Macrophages play a vital role in tissue repair and regeneration following injury. However, the cell fate, dynamic responses, and functions of macrophages from various origins during lung injury and repair are not fully understood. Here, we used genetic lineage tracing and scRNA-seq approaches to explore the temporal and spatial roles of tissue-resident and infiltrating macrophages during pulmonary fibrosis. We observed a sharp reduction in tissue-resident macrophages during the early inflammatory phase, with their numbers stabilizing during recovery. Monocytes contributed substantially to the macrophage population during the fibrotic phase, initially differentiating into interstitial macrophages and later transitioning into alveolar macrophages through a transient state. Genetic ablation of monocytes led to a reduction in the number of infiltrating macrophages and alleviated pulmonary fibrosis. Mechanistically, Notch signaling was negatively correlated with Wnt/β-catenin signaling in the regulation of monocyte recruitment and pulmonary fibrosis. Our study reveals the dynamic contributions and functions of macrophages from various sources in lung injury and regeneration.

Cognitive factors critically influence appetite and food consumption, contributing to the increasing incidence of obesity in modern obesogenic environments. However, the cellular and molecular mechanisms underlying this phenomenon remain poorly understood. Here, using calcium imaging in freely moving mice, we found that neurons in the prelimbic cortex (PrL) underwent activity-dependent plasticity in response to learned environmental cues paired with a high-fat diet (HFD). The activity of these neurons reliably predicted the duration of food consumption. Transcriptomic analyses further revealed significant alterations in ATP metabolic processes in the PrL following HFD-associated learning. Notably, the depletion of AMPKβ2, a subunit of AMPK that senses ATP dynamics, abolished PrL plasticity during HFD associative learning and prevented the cue-driven overconsumption of palatable food. At the circuitry level, the activity of PrL^CaMKIIα+ neuronal projections to orexin neurons in the lateral hypothalamus was required for HFD overconsumption under conditioned contexts. Collectively, our findings elucidate a cellular and molecular framework in a cortical-hypothalamic pathway that regulates cue-evoked HFD overconsumption, highlighting AMPKβ2 as a promising therapeutic target for treating eating disorders.

Group 3 innate lymphoid cells (ILC3s) play crucial roles in maintaining intestinal homeostasis and defending against bacterial infections. However, the epigenetic mechanisms that regulate ILC3 responses are not well understood. In this study, we show that Trmt61a, the methyltransferase responsible for the m¹A58 tRNA modification, is predominantly expressed in ILC3s. We found that specific depletion of TRMT61A in ILC3s leads to dysregulated cell cycle and a reduction in cell numbers. Notably, mice with an ILC3-specific TRMT61A deficiency exhibit dysbiosis, but antibiotic treatment can restore colonic ILC3 levels. Furthermore, these mice exhibit increased susceptibility to experimental intestinal inflammation and enteric bacterial infection. Our findings uncover a previously unrecognized role for TRMT61A mediated m¹A modification in the regulation of intestinal ILC3s, essential for protecting intestinal tissue during inflammation and enhancing innate immunity against enteric pathogens.