The superior cervical ganglion (SCG) innervates multiple effector organs within cranial tissues and elicits responses including pupil dilation, piloerection, vasoconstriction, and inhibition of salivation. Coordinated ac...The superior cervical ganglion (SCG) innervates multiple effector organs within cranial tissues and elicits responses including pupil dilation, piloerection, vasoconstriction, and inhibition of salivation. Coordinated activation of these targets is associated with the display of different emotions; however, the underlying circuit organization and cellular heterogeneity of SCG neurons remain unclear. Here, we combined neuronal tracing with single-cell and spatial transcriptomics to characterize the SCG circuitry and heterogeneity. We found that each SCG neuron innervates a single effector organ. SCG subtypes defined by their projection (P) targets form two major compartments within the ganglia, but individual P-types were intermingled. Mature SCG transcriptomic (T) types emerge postnatally and exhibit rostra-caudal biases. While some T-types were enriched in SCG populations with specific axon projections, they did not show a strict one-to-one correspondence with P-types. These results suggest that individual sympathetic cranial effectors mediating facial emotions are controlled combinatorially by multiple transcriptomic SCG types.
Cisplatin is a mainstay in cancer treatment, but toxicity and resistance limit its potential. Using RNA sequencing (RNA-seq), we show that ovarian cancer cells undergo broad changes in the microtubule cytoskeleton that c...Cisplatin is a mainstay in cancer treatment, but toxicity and resistance limit its potential. Using RNA sequencing (RNA-seq), we show that ovarian cancer cells undergo broad changes in the microtubule cytoskeleton that correlate with resistance. Consistent with this, we find that cisplatin directly impacts microtubule dynamics in vitro and in cells. Paclitaxel counteracts cisplatin and increases resistance. By purifying tubulin from cisplatin-sensitive, -resistant, and -re-sensitized ovarian cancer cells, we demonstrate that resistance acquisition rewires the tubulin code, leading to microtubule stabilization. Furthermore, tubulin polymerization-promoting protein 3 (TPPP3) contributes to resistance. In vitro, TPPP3 synergizes with tubulin isotypes from resistant cells to yield maximal microtubule stabilization in response to cisplatin. Database analysis shows that patients with low TPPP3 levels have improved therapeutic outcome. Our findings implicate TPPP3 and microtubule dysregulation in cisplatin resistance, independent of effects through DNA damage, and have bearing on the etiology of cisplatin-associated neuropathies and ototoxicity.
The specialized types and functions of epithelial cells in the adult small intestine have been well elucidated, but remain poorly understood in the embryonic small intestine. Through integrating single-cell RNA sequencin...The specialized types and functions of epithelial cells in the adult small intestine have been well elucidated, but remain poorly understood in the embryonic small intestine. Through integrating single-cell RNA sequencing with functional studies using mouse and organoid models, we identify small intestinal sentinel progenitor cells (SISPCs), marked by Lysozyme1 (Lyz1), in the embryonic and neonatal mouse small intestine. Distinct from Lyz1 Paneth cells, SISPCs exhibit dynamic spatiotemporal patterning and stemness features during intestinal development. Notably, embryonic SISPCs display strong stemness potential in the proximal small intestine, whereas embryonic Lgr5 cells exhibit greater stem potency in the distal region. In addition, SISPCs play a crucial role in the prenatal intestinal injury repair via the DUSP-p38 signaling axis and contribute to the neonatal antimicrobial defense. Our findings reveal SISPCs play a pivotal role in gut homeostasis and defense during development, and suggest them as potential therapeutic targets for developmental gut disorders.
The complex interplay between nerves, immunity, and tumor progression remains poorly understood, particularly in the context of chemotherapy. Here, we investigated how neural remodeling influences tertiary lymphoid struc...The complex interplay between nerves, immunity, and tumor progression remains poorly understood, particularly in the context of chemotherapy. Here, we investigated how neural remodeling influences tertiary lymphoid structures (TLSs) and clinical outcomes following neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC). Using tissue samples from 86 treatment-naïve and 49 NAT-treated patients with PDAC, we demonstrated that chemotherapy significantly increases both nerve density (ND) and TLS abundance. Notably, nerve-proximal TLSs (N-TLSs) displayed more mature phenotypes and correlated positively with tumor regression. Spatial transcriptomics of nerve regions showed chemotherapy-induced transcriptional reprogramming of Schwann cells, marked by altered myelination programs and elevated pro-inflammatory signaling. The Schwann cell state shift coincides with TLS accumulation, maturation, and enhanced peri-neural immune infiltration. Collectively, our study indicates a spatially organized neuro-immune axis linking neural remodeling to TLS abundance and maturation after chemotherapy and nominates N-TLS abundance as a potential histological biomarker of treatment response in resected PDAC.
Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) wh...Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET, and blue native gels, we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and promotes oligomerization.
The origin and diversification of angiosperms, particularly their ancestral ecological niche, remain an enduring mystery. While competing hypotheses exist, the genomic mechanisms driving repeated transitions to aquatic l...The origin and diversification of angiosperms, particularly their ancestral ecological niche, remain an enduring mystery. While competing hypotheses exist, the genomic mechanisms driving repeated transitions to aquatic life are poorly understood. We assembled chromosome-scale genomes for three early-diverging water lilies-Cabomba caroliniana, Barclaya longifolia, and Brasenia schreberi-integrating them with other Nymphaeales genomes for a comparative analysis. Our findings reveal that aquatic adaptation was shaped by ancient whole-genome duplications and functional remodeling of key gene modules. This includes the expansion of photosynthesis and stress-related families, the contraction of nucleotide-binding leucine-rich repeat (NLR) immune receptors, and metabolic reprogramming of terpene-squalene and other stress-associated secondary pathways. These modifications enhanced energy capture, immunity modulation, and resource efficiency in aquatic environments. Collectively, our results underscore the importance of secondary aquatic adaptation in early water lilies, demonstrating that their distinctive aquatic traits can be parsimoniously explained by evolutionary changes associated with adaptation to submerged habitats.
Shah K, Totty MS, Bach SV
… +19 more, Valentine MR, Chandra A, AlGrain HA, Divecha HR, Miller RA, Siewe FRM, Kwon SH, Del Rosario Alvia I, Ramnauth AD, Tippani M, Tyagi S, Kleinman JE, Collado-Torres L, Han S, Hyde TM, Page SC, Maynard KR, Hicks SC, Martinowich K
The human brain's dorsal anterior cingulate cortex (dACC) is critical in cognitive control, specifically reward processing and conflict monitoring, and regulates fear and pain expression. The dACC is evolutionarily older...The human brain's dorsal anterior cingulate cortex (dACC) is critical in cognitive control, specifically reward processing and conflict monitoring, and regulates fear and pain expression. The dACC is evolutionarily older than more recently specialized neocortical areas, such as the dorsolateral prefrontal cortex (dlPFC). Its evolutionary specializations, including agranularity and presence of von Economo neurons (VENs) are linked to its unique roles in cognitive and emotional processing. We generated paired spatially resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data in ten adult neurotypical donors to define cell types and spatial domains. We used non-negative matrix factorization to project gene expression patterns from the snRNA-seq data onto the SRT data to infer spatial localization. Utilizing publicly available resources, we explored spatial topography, enrichment of disease risk, and connectivity of spatially localized cell types, including VENs. Leveraging dlPFC snRNA-seq and SRT data from the same donors, we compared laminar and molecular specialization between the regions.
Dueker K, Capozzola T, Feng Z
… +35 more, Lin RN, Hurtado J, Bangaru S, Yuan M, Beutler N, Garcia E, He WT, Callaghan S, Avillion G, Vo L, Li X, Torres JL, Musharrafieh R, Song G, Mishra N, Sharma P, Yong P, Anzanello F, Kaczmarek Michaels K, Ben-Akiva E, Silva M, Melo M, Makhdoomi M, Westfall-Gomez E, Rinaldi W, Ferguson M, Safonova Y, Crotty S, Irvine DJ, Rogers T, Ward AB, Briney B, Wilson IA, Burton DR, Andrabi R
In anticipation of future coronavirus (CoV) pandemics, developing vaccines that elicit broadly neutralizing antibodies (bnAbs) against diverse CoVs is critical. Here, we vaccinated rhesus macaques with the SARS-CoV-2 spi...In anticipation of future coronavirus (CoV) pandemics, developing vaccines that elicit broadly neutralizing antibodies (bnAbs) against diverse CoVs is critical. Here, we vaccinated rhesus macaques with the SARS-CoV-2 spike (S)-protein, then boosted with heterologous β-CoV S-proteins to focus responses to common conserved S2 bnAb epitopes. Initial SARS-CoV-2 priming elicited receptor-binding domain (RBD)-focused responses, while MERS-CoV boosting redirected responses toward the S2 region, including the stem-helix bnAb site. Although S2-directed serum cross-neutralization was undetectable and most isolated cross-reactive monoclonal antibodies (mAbs) targeted non-neutralizing epitopes, two S2 stem-helix mAbs were identified from memory B cells. These bnAbs neutralized diverse sarbeco- and merbecoviruses, including MERS-CoV, and conferred robust in vivo protection against SARS-CoV-2 challenge. Structural studies reveal that these macaque bnAbs closely mimic human S2 stem bnAbs induced by infection. These findings provide proof-of-principle for vaccination strategies that elicit broadly protective β-coronavirus responses and highlight non-human primates as a translational model for evaluating S2-targeted immunogens.
Fearon AE, Carter EP, Clayton NS
… +16 more, Wilkes EH, Baker AM, Kapitonova E, Bakhouche BA, Tanner Y, Wang J, Gadaleta E, Chelala C, Moore KM, Marshall JF, Chupin J, Schmid P, Jones JL, Lockley M, Cutillas PR, Grose RP
Alphaviruses are mosquito-borne RNA viruses that pose a significant threat to humans, with risks worsened by global warming. Non-structural protein 3 (nsP3) is critical for alphavirus infection, yet its precise roles rem...Alphaviruses are mosquito-borne RNA viruses that pose a significant threat to humans, with risks worsened by global warming. Non-structural protein 3 (nsP3) is critical for alphavirus infection, yet its precise roles remain poorly defined. Using Venezuelan equine encephalitis virus (VEEV) as a model, this study reveals that alphavirus unique domain (AUD) of nsP3 is essential for its condensation and viral replication. nsP3 forms gel-like condensates to bind to the second Tudor domain of Fragile X-related protein 1 (FXR1), forming replication supporting complexes. FXR1 bridges nsP3 and viral RNA within these condensates, which compartmentalize viral replication independent of protein interactions. Furthermore, UBAP2L was identified as a condensate-resident restriction factor against VEEV. Based on conserved AUD across alphaviruses, we developed a "21 R-AUD" antiviral strategy by fusing TRIM21's RING domain to VEEV's AUD. This approach induces proteasomal degradation of nsP3 condensates and inhibits replication of multiple alphaviruses, establishing conserved nsP3 condensation as a broad-spectrum antiviral target.
Oxidative protein folding in the endoplasmic reticulum (ER) is essential for eukaryotic cells yet generates hydrogen peroxide (HO), a reactive oxygen species. The ER-transmembrane protein that supports ER proteostasis an...Oxidative protein folding in the endoplasmic reticulum (ER) is essential for eukaryotic cells yet generates hydrogen peroxide (HO), a reactive oxygen species. The ER-transmembrane protein that supports ER proteostasis and guards the cytosol for antioxidant defense remains unidentified. Here, we combine AlphaFold2 and functional screens in C. elegans to discover a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting ERGU-1 upregulates HO and NRF2/SKN-1-dependent gene expression. ERGU-1 deficiency also impairs organismal reproduction and behavioral responses to HO. Both C. elegans ERGU-1 and human homolog TMEM161B localize to ER membranes, forming reticular networks. Human and Drosophila homologs of ERGU-1 rescue C. elegans mutant phenotypes, demonstrating ancient and conserved functions. In addition, purified ERGU-1 and TMEM161B exhibit redox-modulated oligomeric states. Together, our results reveal an ER-membrane-specific machinery, suggesting a conserved mechanism for maintaining ER redox homeostasis and proteostasis in animal cells.
The protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine phosphorylase (MTAP)-deleted cancers, where 5'-methylthioadenosine (MTA) accumulation partially inhibits its...The protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine phosphorylase (MTAP)-deleted cancers, where 5'-methylthioadenosine (MTA) accumulation partially inhibits its activity. However, it remains unclear whether other genetic alterations can dictate PRMT5 activity in cancer. Here, we identify liver kinase B1 (LKB1) as an alternative predictor of PRMT5 inhibition in lung cancer independent of MTAP. Mechanistically, LKB1 loss activates salt-inducible kinase 1/2 (SIK1/2)-cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) signaling to upregulate nicotinamide N-methyltransferase (NNMT), creating a "methyl sink" that lowers the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio and attenuates PRMT5 activity. NNMT overexpression is sufficient to induce this hypomorphic PRMT5 state and heighten sensitivity to PRMT5 inhibitors. Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.
Lim G, Kim J, Park D
… +27 more, Lee JH, Roh YJ, Yang M, Lee S, Yang S, Baek S, Park J, Lim HC, Lee JH, Kim S, Seo H, Kim YH, Jung SM, Yang H, Sun P, Lee SE, Kang YE, Park YJ, Son YM, Yi HS, Hong JY, Moita LF, Kang DH, Kim H, Kim C, Yoon SJ, Choi DW
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present a substantial clinical burden, magnified by conditions such as COVID-19. While these conditions provide a model for explori...Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present a substantial clinical burden, magnified by conditions such as COVID-19. While these conditions provide a model for exploring complex inflammatory processes, the environmental factors coordinating these responses remain poorly understood. Here, we employ comprehensive multi-omics and biochemical analyses and identify neutrophil-derived itaconate as an extracellular factor associated with sequential immune cell infiltration, including neutrophils, T cells, and monocytes. Mechanistically, extracellular itaconate metabolically facilitates Kdm5b-associated epigenetic changes at the Il6, Ccl5, and Cxcl10 gene promoters in alveolar macrophages, which are important for immune cell recruitment. Consistent with this, Mrp8-Cre Acod1 mice lacking neutrophil-derived itaconate are significantly protected from ALI-induced inflammation, with similar patterns observed in an Acinetobacter baumannii infection model. Collectively, these findings identify neutrophil-derived itaconate as an environmental factor that epigenetically shapes tiered inflammatory responses in the lung.
Sakuma I, Gaspar RC, Morgan HN
… +14 more, Zheng J, Nasiri AR, Dufour S, Kahn M, Guerra MT, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner DF, Petersen KF, Samuel VT, Tanaka T, Shulman GI
Metabolic dysfunction-associated steatohepatitis (MASH) increases liver-related mortality, and new therapies targeting its underlying mechanisms are warranted. We examined whether two lipid-droplet proteins, CIDEB and CG...Metabolic dysfunction-associated steatohepatitis (MASH) increases liver-related mortality, and new therapies targeting its underlying mechanisms are warranted. We examined whether two lipid-droplet proteins, CIDEB and CGI-58, exert opposing control over MASH by altering cholesterol in liver lipid droplets. Using antisense oligonucleotides, we silenced CIDEB or CGI-58 in the livers of C57BL/6J mice fed a choline-deficient, L-amino acid-defined high-fat diet. CIDEB silencing decreased both triglyceride and cholesterol levels in liver lipid droplets and lowered plasma transaminases and the number of crown-like structures. These protective effects were abrogated by cholesterol supplementation. Conversely, CGI-58 knockdown raised triglyceride and cholesterol levels and exacerbated MASH; bempedoic acid, a cholesterol-synthesis inhibitor, reversed these changes. Dual CIDEB/CGI-58 silencing confirmed that CGI-58 loss abrogated the protective effects of CIDEB knockdown. Our data establish liver lipid-droplet cholesterol as a critical determinant in MASH mediated by CIDEB and CGI-58 and demonstrate that CIDEB knockdown confers protection by enhancing CGI-58-dependent lipolysis.
Li Y, Zhao H, Chen X
… +17 more, Zhang J, Du Q, Shen Y, Zhu C, Zhang D, Lv H, Zhang Y, Huang X, Ge H, Zhang Y, Zafar MI, Yu Y, Zhao X, Chen X, Hu Y, Chen X, Wu B
Repair and regeneration disorder after endometrial injury is the core cause of endometrial diseases. Using a mouse full-thickness endometrial injury model and human endometrial datasets, we performed time-series single-c...Repair and regeneration disorder after endometrial injury is the core cause of endometrial diseases. Using a mouse full-thickness endometrial injury model and human endometrial datasets, we performed time-series single-cell and spatial omics to explore the cellular and molecular dynamics of mouse endometrial regeneration. In the early inflammatory stage (0-4 dpi), macrophages rapidly infiltrate and are indispensable for regeneration. During the middle regenerative stage (4-14 dpi), SFRP4+ stromal cells expand and undergo developmental reprogramming, a conserved mechanism in human normal endometrium but reduced in regenerative defect diseases. Macrophages promote this reprogramming via tumor necrosis factor-alpha (TNF-α), and TNF-α-induced SFRP4+ stromal cells effectively enhance regeneration after transplantation. This study provides a valuable multi-omics resource for understanding endometrial regeneration, with the understanding that further validation is required for clinical applicability.
Tsingas K, Thomas M, Reale M
… +39 more, Xiao M, Wickramasinghe J, Chen Y, Duong B, Lucas A, Thacker G, Li H, Mou H, Ramirez-Salazar E, Elbasir A, Villanueva J, Xu X, Flowers A, Karakousis GC, Miura JT, Mitchell TC, Amaravadi RK, Schuchter LM, Liu S, Long Q, Hoon DSB, Ramos RI, Catbagan JJ, Bustos MA, Gershenwald JE, Simon JM, Wargo JA, Davies MA, Lu Y, Mills GB, Cohen S, Lawless A, Sharova T, Frederick DT, Flaherty KT, Hacohen N, Boland GM, Auslander N, Herlyn M
Melanoma is a common and aggressive cancer, with rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for patients in late-stage disease. Despit...Melanoma is a common and aggressive cancer, with rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for patients in late-stage disease. Despite these advances, many tumors remain refractory, in part due to an incomplete understanding of the genes and pathways gained or lost during melanoma tumorigenesis. To address this gap and provide a broadly useful resource for the scientific community, we established melPDomiX, a multi-omics cohort of melanoma-patient-derived xenografts. By linking mutations with transcriptomic and proteomic features, melPDomiX enables systematic characterization of gain- and loss-of-function alterations in treatment-refractory melanoma. Using multi-omics integration and structural-context representation, we demonstrate how this resource distinguishes gain- from loss-of-function variants and uncovers new candidate melanoma drivers and therapeutic targets. Together, melPDomiX provides a comprehensive, deeply profiled set of tumor models that supports mechanistic discovery and facilitates the development of improved treatments for this devastating heterogeneous malignancy.
The blast fungus Magnaporthe oryzae infects plants using an appressorium that generates force to breach the leaf cuticle. Appressorium development follows a cell-cycle-regulated morphogenetic program requiring autophagy-...The blast fungus Magnaporthe oryzae infects plants using an appressorium that generates force to breach the leaf cuticle. Appressorium development follows a cell-cycle-regulated morphogenetic program requiring autophagy-associated death of the spore. How proliferative growth is coordinated with cell death remains unclear. Here, we show that each conidial cell follows a distinct developmental program essential for infection. Using quantitative live-cell imaging, we tracked 10 organelle types during appressorium morphogenesis in wild-type and Δatg8 mutant strains. Photoactivatable GFP microscopy revealed that mitochondria traffic from a single conidial cell into the appressorium, while the remaining cells undergo autophagy. Organelle inheritance occurs independently of cell-cycle checkpoints but coincides with spore germination. Photoconvertible fluorescence microscopy defined the temporal sequence of organelle movement and de novo biogenesis. Our findings reveal that coordinated spatiotemporal control of autophagy and organelle trafficking is necessary for rice blast infection.
Yang J, Lin Q, Gu D
… +18 more, Gao J, Liu Y, Yang K, Zhu Z, Lu C, Li D, Ci S, Lin F, Wang Q, Qian X, You Y, Zhou Q, Wang X, Lu M, Zhang Q, Chen Y, Tao W, Zhang J
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) promote radioresistance and therapeutic failure, yet the underlying mechanisms remain unclear. Here, we show that he...Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) promote radioresistance and therapeutic failure, yet the underlying mechanisms remain unclear. Here, we show that heat shock protein HSPA6 promotes GSC radioresistance by enhancing GTP synthesis. HSPA6 is induced by irradiation and reduces GSC sensitivity to radiotherapy. HSPA6 interacts with and activates IMPDH2, a key rate-limiting enzyme in purine biosynthesis, thereby promoting GTP synthesis, reducing DNA damage, and enhancing radioresistance. Mechanistically, HSPA6 recruits ROCK2 to phosphorylate and activate IMPDH2 at S416. Pharmacological inhibition of HSPA6 and IMPDH2 combined with irradiation significantly improves survival in mice bearing GBM. Our study uncovers the crucial role of HSPA6/IMPDH2-mediated GTP synthesis in GSC radioresistance and suggests that targeting this axis may improve radiotherapy efficacy for GBM.
Adipocytes are plastic cells with the ability to transition into fibroblast-like cells during tissue repair or physiological remodeling. It is unclear how such transitions are regulated and whether they exemplify cell pl...Adipocytes are plastic cells with the ability to transition into fibroblast-like cells during tissue repair or physiological remodeling. It is unclear how such transitions are regulated and whether they exemplify cell plasticity or merely a transient suppression of adipocyte features. Fibroblasts express platelet-derived growth factor receptors (Pdgfra and Pdgfrb), while adipocytes express adiponectin (Adipoq). Here, we use two-step lineage tracing to label Pdgfra and Pdgfrb cells originating from Adipoq adipocytes. Adipocyte-derived Pdgfr cells (ADPCs) are induced adjacent to skin wounds and contribute to the wound fibroblast population. ADPCs lose adipocyte characteristics and acquire fibroblast characteristics, including collagen expression, smooth muscle actin expression, and cell proliferation. Active PDGFRα signaling in ADPCs increases cell proliferation and improves wound angiogenesis and re-epithelialization, while deletion of Pdgfra has the opposite effect. Wound ADPCs persist as fibroblast-like cells after completion of wound healing, indicating an enduring change rather than a transient downregulation of adipocyte characteristics.
Post-injury inflammation can induce abnormal sensory perception and negative emotions. Previous studies have focused on peripheral and spinal prostaglandins (PGs) in response to chronic pain. Substantially, less is known...Post-injury inflammation can induce abnormal sensory perception and negative emotions. Previous studies have focused on peripheral and spinal prostaglandins (PGs) in response to chronic pain. Substantially, less is known about the role of PGs in the cortex. Here, we found that lipocalin-type prostaglandin D (PGD) synthase was upregulated in the anterior cingulate cortex (ACC) of mice after peripheral inflammation. At the synaptic level, excitatory glutamatergic transmission was selectively enhanced in both the thalamic- and the insular-ACC pathways. These enhanced responses were reversed by blocking PGD receptor DP1. Blocking DP1 in the ACC reduced mechanical and cold hypersensitivity and anxiety-like behaviors after peripheral inflammation. Furthermore, activating NMDARs-AC1 signaling produced L-PGDS. Our results provide direct evidence that the PGD-DP1 pathway contributes to cortical sensitization and reveals a potential therapeutic target for the early phase of peripheral inflammation.