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Abstract
Background Cancer accounts for over 20% of late post-transplant mortality, yet the contribution of genetic susceptibility to post-transplant cancer risk remains unclear. This study investigates germline genetic risk factors for post-transplant cancer in the Finnish population using data from the FinnGen cohort. Methods A pan-cancer polygenic risk score (PRS) was constructed using genetic variants identified in UK and US populations to assess the influence of common germline variants on time to first cancer diagnosis in 1,802 Finnish kidney transplant recipients (KTRs), of whom 317 developed post-transplant cancer. The PRS was first validated in the FinnGen non-transplantation cohort and subsequently applied to KTRs, with replication in lung and liver transplant recipients (n = 476). Functional relevance was explored by assessing associations between the PRS and expression levels of 2,923 plasma proteins in the UK Biobank (n = 53,013). Results Compared to a matched non-transplantation cohort (n = 68,294), KTRs exhibited earlier cancer onset. The PRS was significantly associated with time to first cancer diagnosis in the non-transplantation population (HR 1.04; 95% CI 1.038-1.056; p = 3.75 x 10-25). Among KTRs younger than 40 years, higher PRS was associated with earlier cancer onset (HR, 1.08; 95% CI ,1.01-1.17; p = 0.036), indicating a stronger genetic effect at younger ages. The PRS significantly (Bonferroni < 0.05) altered the regulation of 87 plasma proteins, several of which were known cancer-related markers. Conclusion Inherited genetic predisposition, captured by pan-cancer PRS, may contribute to individual susceptibility to cancer after solid organ transplantation, particularly at younger ages.
Authors
Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen
Abstract
Donnai-Barrow Syndrome (DBS) arises from loss-of-function (LoF) variants in the endocytic receptor LRP2/megalin and is characterized by low molecular weight (LMW) proteinuria and developmental abnormalities. Urinary proteomics of nine DBS patients revealed that the urinary proteome of a DBS patient with the missense variant LRP2 p.C1400R was indistinguishable from that of patients with splice site, nonsense, or frameshift mutations. A CRISPR mouse model of the variant was generated to determine the mechanism of LoF and proteinuria. The mutant LRP2 was expressed and observed to dimerize and localize to the proximal tubule apical membrane. However, both fluid-phase and receptor-mediated endocytosis were impaired in the context of a general perturbation of endocytic flux. Immunofluorescence revealed aberrant endocytic recycling with mislocalized RAB11+ and TFR1+ compartments and enlarged lysosomes. Structural modeling showed the LRP2 assembly likely tolerates the cysteine to arginine substitution at the cell surface, but at endosomal pH the variant introduced steric clashes that may disrupt intramolecular interfaces and disturb receptor recycling. These findings point to the importance of LRP2 recycling for global endocytic flux and offer a blueprint for leveraging patient-specific alleles to dissect proximal tubule function.
Authors
Andrew Beenken, Tian H. Shen, Aryan Ghotra, Hediye Erdjument-Bromage, Jeong Lee, Jared S. Kushner, Rachel E. Sturley, Atlas Khan, Jeffrey R. Arace, Leora Kronenberg, Lucy D. Shen, Gabriel H. Rahmani, Patricia K. Donahoe, Thomas A. Neubert, Frances A. High, Ora A. Weisz, Jonathan Barasch
Abstract
Chronic hyperglycemia induces microvascular complications in patients with type 2 diabetes (T2D), particularly diabetic retinopathy, nephropathy, and neuropathy. We revisited to examine such vascular damage in the pancreas in 3D. Using thick pancreatic tissue slices, we analyzed volumetric intraislet and peri-islet exocrine capillary density (vICD and vECD), as well as interface capillary counts along the islet periphery to quantify vascular integration between the islets and surrounding acinar cells. Contrary to the previous reports, vICD was not homogeneous, but highly heterogeneous across the five species studied (human, monkey, pig, ferret and mouse), especially in smaller islets (15%–80%). vICD became less variable with increasing islet size converging at approximately 20%. With this foundation of islet vascularization, pancreatic tissues from non-diabetic (ND) and T2D subjects consisting of eight age- and sex-matched pairs (age range of 35-65 years with various duration: 0-15 years) were examined. Strikingly, no significant differences in microvasculature were found, where mean vICD (~30%) and mean vECD (~15%) were nearly equivalent between the groups. Capillary integration with respect to islet size was comparable. It suggests that integrated pancreatic blood flow with robust crosstalk between the endocrine and exocrine pancreas may facilitate microvascular preservation in T2D via local distribution of insulin.
Authors
Alex M. Tollefson, Frank R. Marsico, Manami Hara
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, yet the cellular crosstalk driving periductal fibrosis remains poorly defined. This study applied a multi-omics approach integrating spatial transcriptomics, RNA-seq, and proteomics to characterize fibrotic periductal regions and their cell–cell communications. Macrophages (MP) subsets, including monocyte-drived-(Mo)MP and lipid-associated-macrophage (LAM)-like, co-localized with cholangiocytes, lymphocytes, and hepatic stellate cells (HSC1). Cell niche analysis identified periductal regions with elevated fibrotic signals, where cell–cell communication analysis revealed potential MP–HSC interactions involving 17 fibrotic driver genes in MP, including ITGB2, GRN, and CCL21, and 6 fibrotic effector genes in HSC. In validation analyses, bulk RNA-seq data showed higher driver and effector gene expression in PSC with established fibrosis compared to early-stage PSC or healthy control (HC). Plasma proteins encoded by MP driver genes were elevated in PSC and in patients with elevated (≥3.29 kPa) liver stiffness on MR elastography. Furthermore, immunofluorescence and SHG imaging showed enrichment of CD68+/CD18+(ITGB2) macrophages in fibrotic regions of PSC liver biopsies. These findings revealed enrichment of MoMP and LAM-like macrophages in fibrotic regions and suggest that they likely contribute to fibrotic activation of nearby HSCs in PSC.
Authors
Yunguan Wang, David Adeleke, Xiangfei Xie, Zi F. Yang, Xiangya Wang, Giulia Loi, Annika Yang vom Hofe, Manavi Singh, Astha Malik, Ramesh Kudira, Cyd Castro-Rojas, Liva Pfuhler, Mosab Alquraish, Pamela Sylvestre, Jonathan R. Dillman, Andrew T. Trout, Emily R. Miraldi, Alexander G. Miethke
Abstract
High dietary salt intake elevates blood pressure and drives multi-organ damage. However, the molecular programs underlying progressive organ injury remain poorly defined. Here, we present a longitudinal multi-organ transcriptomic atlas of salt-induced hypertensive injury. We profiled kidney cortex, kidney medulla, heart, and liver across four stages spanning early hypertension to advanced pathology in Dahl salt-sensitive rats. We identified dynamic and tissue-specific molecular trajectories, including a shared early proliferative response that converges on proinflammatory and fibrotic remodeling. Notably, we uncovered compartment-specific renal responses, showing that the cortex and medulla, despite their proximity, follow distinct molecular trajectories during disease progression. We further identified 79 stage- and tissue-specific transcription factors that drive gene expression dynamics in salt-induced hypertensive injury. Integration with human genome-wide association studies revealed conserved pathways in endocrine signaling, ion transport, lipid metabolism, and detoxification, establishing cross-species relevance and highlighting mechanistic targets of clinical importance. Compound–transcriptome analysis revealed stage- and organ-specific therapeutic opportunities, prioritizing kinase and epigenetic modulators as candidates to rebalance maladaptive gene programs. Overall, this study provides a resource for understanding molecular mechanisms from early salt-induced hypertension to tissue-specific injury and underscores the need for precision interventions.
Authors
Ratnakar Tiwari, Olha Kravtsova, Lashodya V. Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Steven Didik, Ruslan Bohovyk, Daria V. Ilatovskaya, Oleg Palygin, Alexander Staruschenko
Abstract
Extracellular matrix (ECM) disorder was considered as the result of fibrosis, but it is recently recognized that fibrotic ECM initiates a self-reinforcing circuit and contributes to development of fibrosis. Versican, an ECM component, participates in cell-ECM interaction and ECM regeneration. In pleura, versican is primarily derived from pleural mesothelial cells (PMCs). However, the role and mechanism of versican in pleural fibrosis remained unknown. In this study, versican and versican-mediated pleural viscoelasticity was found elevated in both human and murine pleural fibrotic tissues. Versican knockdown by shRNA prevented increases of viscoelasticity as well as pleural fibrosis. High level of versican and viscoelasticity promoted mesothelial to mesenchymal transition (MesoMT) in PMCs. Mechanistically, increased viscoelasticity induced pleural fibrosis through CD44/USP10/Smad4 mechanotransduction pathway. In conclusion, these results revealed that excessive versican in fibrotic pleural ECM enhanced ECM viscoelasticity, and consequently promoted progression of pleural fibrosis.
Authors
Zi-Heng Jia, Xin-Liang He, Xiao-Lin Cui, Qian Li, Pei-Pei Cheng, Li-Qin Zhao, Shu-Yi Ye, Shi-He Hu, Chen-Yue Lian, He-De Zhang, Li-Mei Liang, Lin-Jie Song, Fan Yu, Liang Xiong, Fei Xiang, Xiaorong Wang, Meng Wang, Xiyong Dai, Hong Ye, Wan-Li Ma
Abstract
Lipotoxicity associated with metabolic dysfunction-associated steatotic liver disease (MASLD) causes dysregulated fatty acid (FA) and glucose metabolism, inducing cellular energy imbalance, oxidative stress (OS), and hepatocellular injury. Interleukin (IL)-10 is altered in MASLD, including increased IL-10 transcripts in peripheral immune cells; however, its role in hepatic responses to lipotoxic stress remains unclear. We evaluated whether IL-10 treatment attenuates lipotoxic injury and MASLD-related phenotypes in vivo and in vitro to reveal MASLD treatment strategies. As MASLD models, in vivo high-fat diet mice and in vitro normal human hepatocytes under palmitic acid exposure, with confirmatory experiments in HepG2 cells, were used and treated with IL-10. We assessed FA and glucose metabolism, OS, and apoptosis with histological changes and mechanisms related to hepatocellular viability/metabolic activity and stress-responsive survival signaling in vitro. IL-10 modulated FA synthesis and β-oxidation, reducing lipid accumulation, and altered glucose metabolic pathways, consistent with improved glucose handling under lipotoxic stress. Furthermore, IL-10 reduced OS and cell death markers while enhancing antioxidant responses, consistent with hepatocellular protection. These data suggest that IL-10 attenuates lipotoxic injury by modulating hepatic response pathways, thereby improving MASLD-related phenotypes, and supports the potential of IL-10 as a therapeutic target for MASLD.
Authors
Akira Kado, Kazuya Okushin, Takeya Tsutsumi, Toshiyuki Kishida, Kazuhiko Ikeuchi, Hiroshi Yotsuyanagi, Kyoji Moriya, Kazuhiko Koike, Mitsuhiro Fujishiro
Abstract
Impaired adhesion and differentiation of keratinocytes is a hallmark of several skin diseases, but only some of the factors that regulate these processes have been identified. Here, we studied the role of isoform-rich dermokine – a wound- and tumor-regulated protein – in keratinocytes using a combination of multi-omics and functional approaches. CRISPR/Cas9-induced knockout of dermokine isoforms in human keratinocytes inhibited differentiation of these cells in three-dimensional organotypic skin cultures, which was confirmed by quantitative proteomics. In two-dimensional monocultures, dermokine deficiency affected the proteome and phosphoproteome as revealed by mass spectrometry. We found reduced abundance of differentiation-specific proteins and increased phosphorylation of cell adhesion protein p120 (catenin-δ1). The adhesive strength of dermokine knockout keratinocytes was impaired, which was rescued by p120 knock-down or ROCK inhibition. Finally, we verified the correlation between decreased dermokine expression and increased p120 phosphorylation in human non-healing wounds. These results identify dermokine as regulator of keratinocyte adhesion and differentiation, involving at least in part its effect on p120 phosphorylation and ROCK. Our data point to a function of dermokine in the pathogenesis of chronic wounds.
Authors
Vahap Canbay, Till Wüstemann, Weihua Tian, Tobias A. Beyer, Camilla Reiter Elbæk, Michael Stumpe, Gaetana Restivo, Chatpakorn Christiansen, Anabel Migenda Herranz, Susanne Mailand, Jürg Hafner, Rune Busk Damgaard, Steffen Goletz, Jörn Dengjel, Ulrich auf dem Keller, Chiara Francavilla
Abstract
Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorders-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1 (HMGB1)-mediated myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes (NRCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids (FA). Consequently, HMGB1 promoted a pro-inflammatory response in macrophages. On the contrary, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9 (AAV9) delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet (UPD). Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.
Authors
Claire Ross, Sanskruti Ravindra Gare, Nasser H. Alatawi, Oveena Fonseka, Xinyi Chen, Jiayan Zhang, Yihua Han, Andrea Ruiz-Velasco, Riham R.E. Abouleisa, Yingjuan Liu, Xiangjun Zhao, Han Xiao, Bernard Keavney, Gareth J. Howell, Tao Wang, Tamer M.A. Mohamed, Elizabeth J. Cartwright, Wei Liu
Abstract
Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues. However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance. We sought agents that reduced conditioning intensity, while promoting durable mixed chimerism after HCT across complete major histocompatibility complex (MHC) mismatch in diabetic mice, permitting islet allotransplantation and diabetes reversal. We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT. Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of GVHD. Thus, we have developed a conditioning regimen to promote allogeneic mixed hematopoietic chimerism and transplanted islet allotolerance that minimizes conditioning radiation and cures diabetes, a significant achievement.
Authors
Stephan A. Ramos, Preksha Bhagchandani, Diego M. Burgos, Xueying Gu, Richard Rodriguez, Nadia Nourin, Martin Neukam, Shiva Pathak, Judith Shizuru, Seung K. Kim
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