Cell Discovery最新文献

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.

The remodeling of mammary glands during pregnancy is essential for initiating lactation. In dairy animals, the overlap of pregnancy and mammary involution triggers a unique process, regenerative remodeling, which is critical for extending lactation duration and enhancing milk production. Unlike the complete regression of lobuloalveolar structures during involution, the regenerative remodeling preserves alveolar structures and promotes rapid mammary gland renewal. However, the cellular and molecular mechanisms underlying such process remain elusive. Here, taking dairy goats (Capra hircus) as a ruminant model, we identified four luminal cell populations through single-cell RNA-sequencing and found a significant reduction in luminal hormone-responsive (LumHR) cells and an increase in luminal secretory precursors (LumSecP) during regenerative remodeling. A reduction of LumHR cells during regenerative remodeling is essential for promoting the accumulation of LumSecP. Goat mammary organoids and in vivo genetic ablation assays suggested that LumHR cells function as a crucial switch for the differentiation of LumSecP to LumSec cells through the prolactin receptor pathway. Furthermore, high levels of IRF1 inhibited while downregulation of IRF1 stimulated the proliferation of LumHR cells. We showed that IRF1 regulated the dynamics of LumHR cells through hormonal signaling targets, including ESRRB. Our findings identified a key cell type responsible for the dynamics of luminal lineages during regenerative remodeling in large mammals and highlighted the potential for accelerating tissue regeneration through targeted modulation of lineage stage-specific regulators.

SARS-CoV-2 infection has raised significant concerns regarding its impact on assisted reproductive technology. We found that oocyte retrieval during acute SARS-CoV-2 infection significantly reduced the rates of good-quality blastocyst formation, but the underlying molecular mechanisms remain poorly understood. To address this, we investigated the effects of maternal acute SARS-CoV-2 infection on preimplantation embryo development and the early offspring hematopoietic system. Using single-cell RNA sequencing (scRNA-seq), we identified developmental delays in morphologically normal blastocysts from infected mothers, characterized by prolonged expression of zygotic genome activation-related genes, downregulation of mTORC1 signaling, and altered energy metabolism, including suppressed oxidative phosphorylation (OXPHOS) and enhanced glycolysis. We further revealed that maternal acute infection induced abnormal methylation/demethylation patterns in preimplantation embryos. To assess the potential long-term impact on offspring, we conducted integrated multi-tissue analyses, including bulk RNA-seq and genome-wide DNA methylation profiling of placental tissues, along with scRNA-seq of umbilical cord blood (UCB) cells from neonates delivered by SARS-CoV-2-infected mothers. Neonates exhibited elevated levels of inflammatory cytokines and an increased abundance of monocytes, indicating an activated myelopoiesis response. In addition, hematopoietic stem and progenitor cells (HSPCs) from UCB showed reduced OXPHOS activity and a skewed differentiation bias toward the myeloid lineage, potentially impacting long-term immune function. Collectively, these findings reveal that maternal acute SARS-CoV-2 infection impairs preimplantation embryo development and leaves a lasting imprint on offspring hematopoietic health through dysregulated energy metabolism, epigenetic modifications, and altered immune responses.

Receptor-like kinases (RLKs) reside on the cell surface and recognize apoplastic colonization by plant-infecting microbes to initiate immune responses. Whether RLKs can also recognize intracellular colonization by viruses to activate antiviral defense mechanisms in plants remains unknown. Here, we report the identification and characterization of a trans-Golgi network/early endosome (TGN/EE)-localized RLK that recognizes viral proteins and inhibits infection in rice. OsVIRK1, a cysteine-rich receptor-like kinase, promotes rice resistance to rice stripe virus (RSV), one of the most devastating viruses of rice. OsVIRK1 transcription is induced in RSV-infected rice, and its protein accumulates through autophosphorylation and redox-mediated regulation. OsVIRK1 physically interacts with the RSV coat protein (CP), a known immune elicitor, and nonstructural protein 3 (NS3), an antiviral RNA-silencing suppressor, at the TGN/EE. OsVIRK1 is required for CP-triggered defense gene expression. It phosphorylates NS3, reducing NS3 accumulation in the cytoplasm and thus repressing its activity as an RNA-silencing suppressor. Our findings suggest that OsVIRK1 recognizes viral proteins at the TGN/EE to inhibit infection by activating plant antiviral immunity and dampening viral counterdefense.