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: 2223
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: 2166
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: 1514
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: 1300
Abstract
Mammalian skin wounds typically heal with a scar, characterized by fibrotic tissue that disrupts original tissue architecture and function. Therapies that limit fibrosis and promote regenerative healing remain a major unmet clinical need. Rosemary extract, particularly in the form of topical oils and creams, has gained widespread public attention for its purported wound-healing properties. However, its efficacy and mechanism of action remain poorly understood. We show in adult wound healing mouse models that an ethanol-based rosemary extract accelerates the speed of wound healing and mitigates fibrosis. Mechanistically, we identify that carnosic acid, a major bioactive component of rosemary leaves, activates the transient receptor potential ankyrin 1 (TRPA1) nociceptor on cutaneous sensory neurons to enhance tissue regeneration. Mice lacking TRPA1 in sensory neurons do not exhibit these pro-regenerative responses, confirming its role as a critical mediator. Together, these findings suggest that topical rosemary extract may represent an effective and accessible therapeutic approach to improve skin repair outcomes.
Authors
Emmanuel Rapp, Jiayi Pang, Borna Saeednia, Stephen Marsh Prouty, Christopher A. Reilly, Thomas H. Leung
Total views: 1293
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: 1292
Abstract
Alzheimer disease (AD) is characterized by plaques and tangles, including calcium dysregulation and glycated products produced by reactive carbonyl compounds. AD brains have increased glyoxalase I (GLO1), a major scavenger of inflammatory carbonyl compounds, at early, but not later, stages of disease. Calcium dysregulation includes calcium leak from phosphorylated ryanodine receptor 2 (pS2808-RyR2), seen in aged macaques and AD mouse models, but the downstream consequences of calcium leak remain unclear. Here, we show that chronic calcium leak is associated with increased GLO1 expression and activity. In macaques, we found age-related increases in GLO1 expression in the prefrontal cortex (PFC), correlating with pS2808-RyR2, and localized to dendrites and astrocytes. To examine the relationship between GLO1 and RyR2, we used S2808D-RyR2 mutant mice exhibiting chronic calcium leak through RyR2, and found increased GLO1 expression and activity in the PFC and hippocampus as early as 1 month and as late as 21 months of age, with a bell-shaped aging curve. These aged S2808D-RyR2 mice demonstrated impaired working memory. As with macaques, GLO1 was expressed in astrocytes and neurons. Proteomics data generated from S2808D-RyR2 synaptosomes confirmed GLO1 upregulation. Altogether, these data suggest potential association between GLO1 and chronic calcium leak, providing resilience in early stages of aging.
Authors
Elizabeth Woo, Dibyadeep Datta, Shveta Bathla, Hannah Beatty, Pinar Caglayan, Ashley Kristant Albizu, TuKiet T. Lam, Jean Kanyo, Mary Kate Joyce, Shannon Leslie, Stacy Uchendu, Jonathan DeLong, Qinyue Stacy Guan, Jiaxin Li, Efrat Abramson, Alison L. Herman, Dawson Cooper, Pawel Licznerski, Tamas L. Horvath, Elizabeth A. Jonas, Angus C. Nairn, Amy F.T. Arnsten, Lauren H. Sansing
Total views: 1273
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: 1263
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: 1189
Abstract
Peripheral helper T (Tph) and follicular helper T (Tfh) cells are key regulators of B cell differentiation and antibody production, making them promising targets for autoimmune disease treatment. However, their differentiation mechanisms differ significantly between humans and mice, limiting drug validation in mouse models. Here, we present a simple and effective method for in vivo proliferation of human Tph/Tfh and B cells. We discovered that after depleting CD8+ T cells of human peripheral blood mononuclear cell–transferred immunodeficient mice (CD8TΔhPBMC mice), human Tph/Tfh cells and B cells proliferated markedly in the spleen compared with those in human PBMC–transferred immunodeficient mice (hPBMC mice). Transcriptome analysis confirmed proliferating cells’ close resemblance to human Tph/Tfh cells. Furthermore, multicolor flow cytometry revealed CXCL13+ Tph cells infiltrating Sjögren’s syndrome–associated (SjS-associated) organs, such as salivary glands. Single-cell RNA sequencing identified IL-21+CXCL13+IFN-γ+ICOS+TIGIT+GPR56+ Tph cells in the salivary glands. These findings are consistent with reduced saliva volume and elevated SjS markers, such as anti-SSA antibody, in these mice, which were both ameliorated by immunosuppressants. In vitro, CD8+ T cells from hPBMC mice induced B cell apoptosis and inhibited Tph/Tfh differentiation. This model advances understanding of human Tph/Tfh cell biology and offers a valuable platform for studying SjS and therapeutic targets.
Authors
Mariam Piruzyan, Sota Fujimori, Ryota Sato, Yuki Imura, Sachiko Mochiduki, Kana Takemoto, Akiko Nishidate, Yuzo Koda
Total views: 1145
