Top read articles in the last 30 days
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Abstract
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
Authors
Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin
Total views: 2017
Abstract
Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent IFN responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by preexisting vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited higher immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines were more immunogenic than the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.
Authors
Bakare Awakoaiye, Shiyi Li, Sarah Sanchez, Tanushree Dangi, Nahid Irani, Laura Arroyo, Gabriel Arellano, Shadi Mohammadabadi, Malika Aid, Pablo Penaloza-MacMaster
Total views: 1770
Abstract
Pulmonary arterial hypertension (PAH) is a rare and incurable disease characterized by progressive narrowing of pulmonary arteries (PA), resulting in right ventricular (RV) hypertrophy, RV failure, and eventually death. Orai1 inhibition has emerged as promising therapeutic approach to mitigate PAH. In this study, we investigated the efficacy of a clinically applicable selective Orai1 inhibitor, CM5480, and its effects when combined with standard PAH therapies in a preclinical PAH model. In male and female monocrotaline PAH-rats, CM5480 monotherapy improved hemodynamics, PA, and RV remodeling, as confirmed by RV catheterization, echocardiography, histology, and unbiased RNA-Seq. Standard PAH therapies, ambrisentan or sildenafil, achieved modest improvements in experimental PAH. In contrast, combination therapies with CM5480 yielded significantly greater benefits in reducing PA remodeling and improving cardiac function compared with monotherapies. Furthermore, in vitro experiments showed that Orai1 knockdown reduced pulmonary endothelial cell dysfunction in PAH and that the Orai1 pathway is independent of standard PAH-targeted pathways in PA smooth muscle cells (PASMCs). Finally, we found enhanced Orai1 expression/function in PASMCs and pulmonary vein SMCs from patients with pulmonary veno-occlusive disease. These findings suggest that Orai1 inhibition represents a potentially novel and complementary therapeutic strategy for PAH by acting at pulmonary vascular and RV levels.
Authors
Anaïs Saint-Martin Willer, Grégoire Ruffenach, Bastien Masson, Kristelle El Jekmek, Angèle Boët, Rui Adão, Mathieu Gourmelon, Antoine Beauvais, Jessica Sabourin, Mary Dutheil, Maria-Rosa Ghigna, Laurent Tesson, Séverine Ménoret, Ignacio Anegon, Fabrice Bauer, Vincent de Montpréville, Sudarshan Hebbar, Carmen Brás-Silva, Kenneth Stauderman, Marc Humbert, Olaf Mercier, David Montani, Véronique Capuano, Fabrice Antigny
Total views: 1527
Abstract
Glomerular inflammation and podocyte loss are the hallmarks of chronic kidney disease (CKD) progression. Understanding how podocytes and their microenvironment regulate inflammation is critical for developing effective therapies. In this study, we identified C-C chemokine ligand 5 (CCL5) as an inflammatory mediator elevated in injured podocytes, based on analyses of both human kidney biopsies and mouse models of CKD. We discovered that CCL5 exerts paradoxical effects in nephropathy; while it protects podocytes in vitro, it exacerbates glomerular injury in vivo. Recombinant CCL5 and podocyte-specific CCL5 overexpression promoted cell survival and reduced apoptosis in cultured podocytes. However, in adriamycin-induced nephropathy, CCL5 worsened glomerular injury, increasing proteinuria, glomerulosclerosis, and podocyte loss. Bone marrow (BM) transplantation experiments revealed that CCL5 in BM-derived cells — not kidney-resident cells — drove disease progression. CCL5 deficiency in BM-derived cells conferred protection by increasing reparative M2 macrophages, whereas endogenous CCL5 promoted M1 polarization, inhibited M2 differentiation, and triggered M2-to-M1 transition. These findings demonstrate that while CCL5 supports podocyte survival, its expression in BM-derived cells promotes inflammatory macrophage phenotypes and glomerular injury. The harmful immune effects of CCL5 in BM-derived cells outweigh its podocyte-protective role, highlighting the importance of cell-targeted strategies to mitigate kidney damage.
Authors
Ika N. Kadariswantiningsih, Issei Okunaga, Kaho Yamasaki, Maulana A. Empitu, Hiroyuki Yamada, Shin-ichi Makino, Akitsu Hotta, Hideo Yagita, Masashi Aizawa, Ryo Koyama-Nasu, Motoko Y. Kimura, Narihito Tatsumoto, Katsuhiko Asanuma
Total views: 1339
Abstract
BACKGROUND Icosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), reduces cardiovascular disease (CVD), but the mechanism remains elusive. We examined the effect of IPE supplementation on lipoprotein subclasses, lipidomes, and pro-atherogenic properties.METHODS Using 3 independent metabolomic platforms, we examined the effect of high-dose IPE supplementation for 28 days on fatty acid profiles, lipoprotein subclasses, lipidomes, and pro-atherogenic properties in normolipidemic volunteers (n = 38).RESULTS IPE supplementation increased lipoprotein EPA on average 4-fold within 7 days, returning to baseline after a 7-day washout. Notably, the incorporation displayed marked interindividual variance, negatively correlating with baseline levels. We identified persistent participant-specific lipoprotein fingerprints despite uniform IPE-induced lipidome remodeling across all lipoprotein classes. This remodeling resulted in reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids, resulting in reduced clinical risk markers, including triglyceride, remnant cholesterol, and apolipoprotein B (apoB) levels and 10-year CVD risk score. Of the pro-atherogenic properties tested, IPE significantly reduced apoB lipoprotein binding to proteoglycans, which correlated with lower apoB particle concentration, cholesterol content, and specific lipid species in LDL, including phosphatidylcholine 38:3 previously associated with CVD.CONCLUSION These findings highlight IPE’s rapid, uniform remodeling of lipoproteins and reduced proteoglycan binding, likely contributing to previously observed CVD risk reduction. Persistent interindividual lipidome signatures underscore the potential for personalized therapeutic approaches in atherosclerotic CVD treatment.TRIAL REGISTRATION NCT04152291.FUNDING Jenny and Antti Wihuri Foundation, Research Council of Finland, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Emil Aaltonen Foundation, Ida Montin Foundation, Novo Nordisk Foundation, Finnish Cultural Foundation, and Jane and Aatos Erkko Foundation.
Authors
Lauri Äikäs, Petri T. Kovanen, Martina B. Lorey, Reijo Laaksonen, Minna Holopainen, Hanna Ruhanen, Reijo Käkelä, Matti Jauhiainen, Martin Hermansson, Katariina Öörni
Total views: 1247
Abstract
Elexacaftor/tezacaftor/ivacaftor (ETI) cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has led to rapid and substantial improvements in cystic fibrosis (CF) airway disease. Underlying molecular and cellular mechanisms, long-term efficacy, and ability to reverse airway epithelial remodeling in established disease remain unclear. Longitudinal nasal brushes from an adult CF cohort were used to evaluate gene expression, cellular composition, stem cell function, and microbiome changes at baseline and at 6 months and 2 years after ETI. The baseline to 6 month span showed a massive downregulation of extensive neutrophilic inflammatory gene expression programs that correlated with increased pulmonary function and decreased sinusitis. Primary airway epithelial stem cell cultures from matched donor samples showed partially improved differentiation and barrier capacity at 6 months. Although clinical outcomes remained stable during the 6 month to 2 year span, transcriptional changes revealed a resurgence of baseline inflammatory programs. The time course of gene expression was consistent with ongoing normalization of epithelial remodeling. Relative abundance of Pseudomonas also decreased during the time course. These data suggest that ETI rectifies inflammation, epithelial remodeling, and bacterial infection in the airways, but resurgence of inflammatory gene expression may indicate ongoing inflammation, potentially presaging disease progression with long-term therapy.
Authors
Eszter K. Vladar, Austin E. Gillen, Sangya Yadav, Mikayla R. Murphree, David Baraghoshi, J. Kirk Harris, Elmar Pruesse, Sierra S. Niemiec, Alexandra W.M. Wilson, Katherine B. Hisert, Stephen M. Humphries, Matthew Strand, David A. Lynch, Max A. Seibold, Daniel M. Beswick, Jennifer L. Taylor-Cousar
Total views: 1212
Abstract
BACKGROUND Accurate prognostic assays for COVID-19 represent an unmet clinical need. We sought to identify and validate early parsimonious transcriptomic signatures that accurately predict fatal outcomes.METHODS We studied 894 patients enrolled in the prospective, multicenter Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) with peripheral blood mononuclear cells (PBMC) and nasal swabs collected within 48 hours of admission. Host gene expression was measured with RNA-Seq. We trained parsimonious prognostic classifiers incorporating host gene expression, age, and SARS-CoV-2 viral load to predict 28-day mortality in 70% of the cohort. Classifier performance was determined in the remaining 30% and externally validated in a contemporary COVID-19 cohort (n = 137) with vaccinated patients.RESULTS Fatal COVID-19 was characterized by 4,189 differentially expressed genes in the peripheral blood. A COVID-specific 3-gene peripheral blood classifier (CD83, ATP1B2, DAAM2) combined with age and SARS-CoV-2 viral load achieved an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI, 0.82–0.94). A 3-gene nasal classifier (SLC5A5, CD200R1, FCER1A), in comparison, yielded an AUC of 0.74 (95% CI, 0.64–0.83). Notably, OLAH, the most strongly upregulated gene in both PBMC and nasal swab and recently implicated in severe viral infection pathogenesis, yielded AUCs of 0.86 (0.79–0.93) and 0.78 (95% CI, 0.69–0.86), respectively. Both peripheral blood classifiers demonstrated comparable performance in an independent contemporary cohort of vaccinated patients (AUCs 0.74–0.80).CONCLUSION Our parsimonious blood- and nasal-based classifiers accurately predicted COVID-19 mortality and merit further study as accessible prognostic tools to guide triage, resource allocation, and early therapeutic interventions.FUNDING NIH: 5R01AI135803-03, R35HL140026, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, 5T32DA018926-18, and K0826161611. National Institute of Allergy and Infectious Diseases, NIH: 3U19AI1289130, U19AI128913-04S1, and R01AI122220. National Center for Advancing Translational Sciences, NIH: UM1TR004528. The National Science Foundation: DMS2310836. The Chan Zuckerberg Biohub San Francisco.
Authors
Rithwik Narendra, Emily C. Lydon, Hoang Van Phan, Natasha Spottiswoode, Lucile P. Neyton, Joann Diray-Arce, IMPACC Network, COMET Consortium, EARLI Consortium, Patrice M. Becker, Seunghee Kim-Schulze, Annmarie Hoch, Harry Pickering, Patrick van Zalm, Charles B. Cairns, Matthew C. Altman, Alison D. Augustine, Steve Bosinger, Walter Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff, Bjoern Peters, Nadine Rouphael, Ruth R. Montgomery, Elaine Reed, Joanna Schaenman, Hanno Steen, Ofer Levy, Sidney C. Haller, David Erle, Carolyn M. Hendrickson, Matthew F. Krummel, Michael A. Matthay, Prescott Woodruff, Elias K. Haddad, Carolyn S. Calfee, Charles R. Langelier
Total views: 1146
Abstract
Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. These transcriptional changes were confirmed by orthogonal imaging techniques and biochemical assays. Single-nuclei RNA sequencing and spatial transcriptomics, both the first of their kind to our knowledge from Alport mice, showed that NAD+ supplementation restored FAO in proximal tubule cells. Finally, we also report, for the first time to our knowledge, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
Authors
Bryce A. Jones, Debora L. Gisch, Komuraiah Myakala, Amber Sadiq, Ying-Hua Cheng, Elizaveta Taranenko, Julia Panov, Kyle Korolowicz, Ricardo Melo Ferreira, Xiaoping Yang, Briana A. Santo, Katherine C. Allen, Teruhiko Yoshida, Xiaoxin X. Wang, Avi Z. Rosenberg, Sanjay Jain, Michael T. Eadon, Moshe Levi
Total views: 1138
Abstract
Juvenile idiopathic arthritis (JIA) is the most prevalent chronic inflammatory arthritis of childhood, yet the spatial organization in the synovium remains poorly understood. Here, we perform subcellular-resolution spatial transcriptomic profiling of synovial tissue from patients with active JIA. We identify diverse immune and stromal cell populations and reconstruct spatially defined cellular niches. Applying a newly developed spatial colocalization analysis pipeline, we uncover microanatomical structures, including endothelial–fibroblast interactions mediated by NOTCH signalling, and a CXCL9-CXCR3 signaling axis between inflammatory macrophages and CD8+ T cells, alongside the characterization of other resident macrophage subsets. We also detect and characterize tertiary lymphoid structures marked by CXCL13-CXCR5 and CCL19-mediated signaling from Tph cells and immunoregulatory dendritic cells, analogous to those observed in other autoimmune diseases. Finally, comparative analysis with rheumatoid arthritis reveals JIA-enriched cell states, including NOTCH3+ and CXCL12+ sublining fibroblasts, suggesting potentially differential inflammatory programs in pediatric versus adult arthritis. These findings provide a spatially resolved molecular framework of JIA synovitis and introduce a generalizable computational pipeline for spatial colocalization analysis in tissue inflammation.
Authors
Jun Inamo, Roselyn Fierkens, Michael R. Clay, Anna Helena Jonsson, Clara Lin, Kari Hayes, Nathan D. Rogers, Heather Leach, Kentaro Yomogida
Total views: 1055
Abstract
BACKGROUND Among people living with HIV (PLWH), immunological nonresponders (INR) fail to adequately restore CD4+ T cell counts despite effective antiretroviral therapy (ART), placing them at greater risk for adverse outcomes and reduced vaccine efficacy. We aimed to study the robustness and longevity of vaccine-induced virus-specific cellular immune responses in INR.METHODS Virus-specific CD8+ T cell responses were analyzed in INR (CD4+ T cell count < 300 cells/μL) and immunological responders (IR) (CD4+ T cell count > 500 cells/μL), receiving ART, and HIV-uninfected controls following COVID-19 mRNA vaccination and infection. Virus-specific CD8+ T cells were characterized using peptide-loaded MHC I tetramer technology, after in vitro expansion and cytokine production assays. Virus-specific CD4+ T cells and IgG levels were determined by activation-induced marker (AIM) assay and ELISA, respectively.RESULTS We demonstrated that, while long-lasting virus-specific cellular immune responses were generated in INR, CD8+ T cell immunity remained limited compared with robust CD4+ T cell reactivity. CD8+ T cell responses in INR exhibited reduced breadth and frequency, accompanied by altered memory differentiation and suboptimal activation and effector response upon antigen exposure. This deficiency correlated with low CD4+ T cell counts, independent of other disease markers, highlighting the pivotal role of CD4+ T cells in orchestrating vaccine-induced immunity. Notably, repeated booster vaccinations enhanced virus-specific CD8+ T cell responses.CONCLUSION INR elicit limited vaccine-induced virus-specific CD8+ T cell immunity, but booster vaccinations can enhance these responses, suggesting better immune outcomes with tailored vaccination strategies.FUNDING Helmholtz Society, German Research Foundation, Federal Ministry of Education and Research.
Authors
Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann
Total views: 1005
