Top read articles in the last 30 days
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Abstract
Pulmonary arterial hypertension (PAH) is a progressive vascular syndrome characterized by aberrant signaling, severe pulmonary artery remodeling, and right ventricular (RV) failure, a major driver of morbidity and mortality. Dysregulation of the apelinergic pathway has been implicated in pulmonary vascular remodeling in PAH. Using a sugen-hypoxia rat model of PAH, we assessed the ability of a potentially novel apelin analog, resistant to native peptidase degradation, to reverse the pathological hallmarks of PAH and RV dysfunction. Apelin analog therapy corrected the vascular lesions in the lungs and nearly normalized pulmonary arterial pressures. Early cardiorenal syndrome, RV dilation, and dysfunction, as well as RV cardiomyocyte and fibroblast activation induced by pressure overload, were also reversed by apelin analog treatment. Single-nucleus RNA-seq of the lungs and RV revealed apelin-analog treatment activated several protective pathways, including rebalancing protective bone morphogenetic protein receptor type 2 (BMPR2) signaling to counteract excessive pathogenic TGF-β receptor 2 (TGFBR2) activity in PAH. These findings highlight the therapeutic potential of exogenous apelin in reversing pulmonary vascular and cardiac pathologies in PAH and support further investigation to evaluate the clinical benefits of apelin analog treatment in patients with PAH and RV failure.
Authors
Jennie Vu, Pavel Zhabyeyev, Kemar J. Brown, Joshua Gorham, Daniel M. DeLaughter, Huachen Chen, Thilina U. Jayawardena, Ander Vergara, Maria Alexiou, Anjalee Wijewardane, Conrad Fischer, Charlotte Avet, Abby Ewasiuk, Faqi Wang, Mark C. Chappell, Yuri Kim, Michel Bouvier, John C. Vederas, Christine E. Seidman, Jonathan G. Seidman, Gavin Y. Oudit
Total views: 4540
Abstract
DNA damage and the cGAS/STING innate immunity pathway have been associated with fibrosis in systemic sclerosis (SSc), but a cause-and-effect role has not been established. Here we report the effects of TY1, a noncoding RNA drug of the exomer class that suppresses DNA damage and thereby inhibits cGAS/STING, in human SSc cells and in 2 preclinical models of SSc. Macrophages from patients with SSc exhibited high levels of phosphorylated DNA damage, cGAS, 2’3’-cGAMP, STING, and IFNs, all of which decreased after exposure to TY1. In mice that had been injected s.c. with bleomycin to model SSc, exercise tolerance, cardiac function, lung hydroxyproline, and skin thickness reverted to normal levels after oral administration of TY1. Similar therapeutic benefits were evident in the genetic tsk-1 mouse model of SSc. TY1 attenuated fibrosis and/or fibrotic gene expression in both mouse models of SSc and in human SSc skin fibroblasts. Our findings support the hypothesis that cGAS/STING, activated by DNA damage, is a key driver of fibrosis in SSc.
Authors
Xaviar M. Jones, Salwa Soussi, Alessandra Ciullo, Kara Tsi, Weixin Liu, Liang Li, Mario Fournier, Thassio Mesquita, Alberto M. Marchevsky, Nunzio Bottini, Francesco Boin, Ahmed G.E. Ibrahim, Eduardo Marbán
Total views: 4255
Abstract
Renin cells are essential for survival and serve as key regulators of blood pressure and fluid-electrolyte homeostasis. Their function and identity are dependent on signals from their local microenvironment afforded by neighboring cells and nerves. Whether and how renin cells contribute to the development and maintenance of this microenvironment remains unclear. Because renin cells are rare — 0.01 % of kidney cells — conventional histological approaches cannot capture their interaction with nerve fibers and surrounding cells within the nephron and its vasculature. Using high-resolution 3D imaging, cell-specific multicolor reporter mice, single-cell RNA-seq, and conditional gene deletions, we mapped how renin cells assemble within arterioles and communicate with axon fibers to organize the growth and orientation of the kidney arterioles during development and disease. This coinductive process is mediated by Ngf produced by renin cell precursors and is necessary for renin cell survival and innervation. Interestingly, renin enzymatic insufficiency elevates Ngf and drives arteriolar hypertrophy with aberrant axon sprouting and hyperinnervation. These findings indicate that renin cells regulate kidney neurovascular development, revealing them as active organizers of their local neuroregulatory microenvironment in health and disease.
Authors
Manako Yamaguchi, Georgina Gyarmati, Liam McLaughlin, Hiroki Yamaguchi, Jason P. Smith, Lucas Ferreira de Almeida, Daisuke Matsuoka, Alexandre G. Martini, Sara M. Wilmsen, Sijie Hao, Kazuki Tainaka, Silvia Medrano, Sanjay Jain, Janos Peti-Peterdi, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
Total views: 3374
Abstract
BACKGROUND Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), but the diagnosis may be missed as kidney biopsies are rarely obtained when acute tubular injury (ATI) is suspected.METHODS The Kidney Precision Medicine Project is a cohort study that obtains kidney biopsies from individuals with AKI, which undergo pathologic and molecular interrogation. We compared ATI and AIN cases among the first 60 AKI participants.RESULTS On clinicopathologic adjudication, 30 patients (50%) had a primary adjudicated diagnosis of ATI, 13 (22%) patients had AIN, 9 (15%) had diabetic nephropathy, and 3 (5%) had other conditions. There were increased interstitial white blood cells and tubulitis (P < 0.05 for both) in AIN compared with ATI. Prior to biopsy, the treating clinician suspected ATI in 83% of the cases with adjudicated ATI, while the treating clinician suspected AIN in 54% of the cases with AIN. Tissue transcriptomic signatures showed enrichment of proinflammatory signaling and increased expression of CXCL9, a chemokine induced by IFN-γ, in myeloid cells of participants with AIN. CXCL9 localized to inflammatory infiltration in spatial transcriptomic data.CONCLUSION Adjudication of kidney biopsies revealed distinct pathologic and molecular profiles between ATI and AIN. Kidney biopsy should be considered more frequently in AKI, as AIN is clinically underrecognized.TRIAL REGISTRATION ClinicalTrials.gov NCT04334707.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937.
Authors
Jennifer A. Schaub, Rajasree Menon, Ricardo Melo Ferreira, Elizabeth Kiernan, Insa M. Schmidt, Christine P. Limonte, Soumya Yennapureddy, Ying-Hua Cheng, Leal Herlitz, Avi Z. Rosenberg, Joel M. Henderson, Kelly D. Smith, Jeffrey B. Hodgin, Edgar Otto, Gilbert W. Moeckel, Lloyd G. Cantley, Suman Setty, Ulysses G.J. Balis, Dawit Demeke, Agnes B. Fogo, Andrew S. Bomback, Vivette D. D’Agati, Isaac E. Stillman, Jose R. Torrealba, Allen R. Hendricks, Erika Bracamonte, Vanessa Moreno, Pavan Bhatraju, Amy K. Mottl, Frank C. Brosius, Bijin Thajudeen, Steven G. Coca, Paul M. Palevsky, Parmjeet S. Randhawa, Raghavan Murugan, Laura Barisoni, Charles E. Alpers, Steven Menez, F. Perry Wilson, Dennis G. Moledina, Michael T. Eadon, Matthias Kretzler, Jonathan Himmelfarb, Chirag R. Parikh, the Kidney Precision Medicine Project
Total views: 3279
Abstract
To identify therapeutic targets limiting glioblastoma invasion, we applied druggable genome CRISPRi screens and multiomic analysis to patient-derived glioblastoma cells in micro-dissectible biomimetic 3D hydrogels that permitted separation and analysis of core versus invasive fractions. Of 2,550 genes screened, 12 encoded druggable targets whose suppression limited invasion, of which AURKB (encoding aurora kinase B) and ACP1 (encoding low molecular weight protein tyrosine phosphatase, LMW-PTP) were validated in neurosphere assays and in vivo. Proximity labeling identified cortactin as a link between LMW-PTP and aurora B, and we observed that cortactin underwent serine phosphorylation by aurora B and tyrosine dephosphorylation by LMW-PTP. Targeting ACP1 or AURKB via CRISPRi or inhibitors in culture and in vivo shifted the cortactin phosphorylation balance in glioblastoma, reducing levels of cortactin and the actin-related protein 2/3 (Arp2/3) complex that mediates cortactin-induced actin stabilization, thereby reducing actin-cortactin-Arp2/3 colocalization and subsequent actin polymerization. AURKB or ACP1 targeting shifted actin from cytoplasm to the nucleus, reducing mesenchymal gene expression. Biophysical analysis implicated AURKB in glioblastoma cell adhesion and stiffness needed for initial migration and ACP1 in mechanical stress resistance required for later migration. These findings revealed a targetable axis balancing kinase and phosphatase activities to regulate actin polymerization during glioblastoma invasion.
Authors
Mufeng Hu, Anna Weldy, Isabella M. Lovalvo, Erin A. Akins, Saket Jain, Alexander Chang, Ankita Sati, Meeki Lad, Austin Lui, Akhil Rajidi, Ameya Kothekar, Erika A. Ding, Juan A. Oses Prieto, Pablo Estevez, Alma L. Burlingame, Sanjay Kumar, Manish K. Aghi
Total views: 3260
Abstract
Alcohol-associated liver disease (ALD) is a growing global health concern, with alcohol-associated hepatitis (AH) leading to the highest morbidity and mortality. Available therapies are limited and often inadequate. Platelets contribute in a variety of ways to liver disease pathogenesis, but their role in AH remains largely unexplored. In this study, we addressed the hypothesis that platelets contribute to pathological inflammation in AH. Using patient samples and a multiomics approach, we found that platelets undergo proinflammatory transcriptomic and proteomic changes in AH, with 2 alarmins, S100A8 and S100A9, being among the top upregulated genes/proteins. Additionally, the abundance of platelet-derived microparticles containing S100A8 and S100A9 in AH patient plasma was increased and correlated with disease severity (assessed by model for end-stage liver disease sodium [MELD-Na]) and endotheliopathy (assessed by ICAM1, CXCL8, and vWF). We mechanistically linked S100A9 with endotheliopathy via crosstalk between primary human liver sinusoidal endothelial cells and primary human monocytes. We also demonstrated that IL-6 upregulates S100A9 in megakaryocytic cells in a JAK/STAT-dependent manner, modeling changes occurring in the bone marrow in patients with AH. Our studies establish proinflammatory platelets as important contributors to AH pathology. Moreover, antiplatelet agents — or, more specifically, S100A9 targeted drugs — are potential therapeutic strategies in AH.
Authors
Fallyn Kirlin, Nima Fattahi, Rolando Garcia-Milian, Florine Collin, Weiwei Wang, Yohan Kim, Fabrice Lucien, Zhaoli Sun, TuKiet T. Lam, John Hwa, Yasuko Iwakiri, Matthew J. McConnell
Total views: 3168
Abstract
Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) has enhanced our understanding of host immune mechanisms in small cohorts, particularly in diseases with complex and heterogeneous immune responses such as sepsis. However, standard PBMC isolation from blood requires technical expertise and over 2 hours of on-site processing using Ficoll density gradient separation (“Ficoll”) for scRNA-seq compatibility, precluding large-scale sample collection at most clinical sites. To minimize on-site processing, we developed cryopreservation with PBMC recovery offsite (Cryo-PRO), a method of immediate on-site whole-blood cryopreservation and subsequent batched PBMC isolation in a central laboratory prior to sequencing. We compared multimodal single-cell immune profiling results from samples processed using Cryo-PRO versus standard on-site Ficoll separation in 23 patients with sepsis. Key outputs, including cell substate fractions, marker genes, and surface protein expression were similar for each method across multiple cell types and substates, including an important monocyte substate enriched in patients with sepsis. Capture of T cell receptor transcripts was also comparable across both methods. Cryo-PRO reduced on-site sample processing time from more than 2 hours to less than 15 minutes and was reproducible across 2 enrollment sites, thus demonstrating potential for expanding multimodal single-cell analyses in multicenter studies of sepsis and other diseases.
Authors
Alyssa K. DuBois, Pierre O. Ankomah, Alexis C. Campbell, Renee Hua, Olivia K. Nelson, Christopher A. Zeuthen, M. Kartik Das, Shira Mann, Abigail Mauermann, Blair A. Parry, Nathan I. Shapiro, Michael R. Filbin, Roby P. Bhattacharyya
Total views: 3050
Abstract
Chronic, non-healing wounds are a severe diabetic complication. The underlying mechanisms are not fully understood, and the role of ATF7 in this context has not been well characterized. In our study, we utilized db/db diabetic mice and AAV-mediated keratinocyte-specific Atf7 overexpression in vivo. HaCaT keratinocyte/THP-1 macrophage cocultures under high glucose were used in vitro. Our results showed that ATF7 was upregulated in diabetic wounds. Keratinocyte-specific Atf7 overexpression accelerated diabetic wound closure, enhanced re-epithelialization, granulation tissue formation, and keratinocyte proliferation, while suppressing macrophage M1 polarization and inflammation. Multiomics screening identified NOTCH1 as a key ATF7 target. ATF7 transcriptionally repressed NOTCH1 by recruiting Suv39h1, increasing H3K9me3 at the NOTCH1 promoter. This reduced NOTCH1 protein and its active intracellular domain (N1ICD) within keratinocyte-derived exosomes. ATF7-overexpressing keratinocyte exosomes carried less N1ICD, leading to decreased N1ICD transfer to macrophages and subsequent inhibition of M1 polarization. Notably, local injection of exosomes from ATF7-overexpressing keratinocytes accelerated wound healing in db/db mice. In summary, ATF7 promotes diabetic wound healing by repressing NOTCH1 transcription via H3K9me3, thereby reducing exosomal N1ICD secretion from keratinocytes and inhibiting macrophage M1 polarization. This identifies the ATF7/NOTCH1/exosome axis as a therapeutic target.
Authors
Pengcheng Xu, Yuan Xue, Linlin Feng, Jingwen Kuang, Xiaochen Hu, Huiyi Tang, Biao Cheng, Limin Wei
Total views: 2988
Abstract
Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterized by elevated pressure in pulmonary arteries, eventually leading to right ventricular failure. Approximately 50% of pediatric disease and 20% of adult disease can be linked to a genetic mutation, with nearly 70% of these cases involving mutations in the bone morphogenetic protein receptor type 2 (BMPR2) locus. Investigations using rodent models have made substantial advances in our understanding of BMPR2 signaling; however, limited data exist regarding the onset and course of PAH, and etiologies for phenotypic expression in these patients remain unknown. In this work, we describe the development of an ovine model of heritable PAH. Because homozygous disruption of BMPR2 is embryonic lethal, we developed heterozygous BMPR2-edited (BMPR2+/–) sheep by using a PAM-disrupting synonymous single-stranded oligodeoxyribonucleotide alongside a single guide RNA and Cas9-mediated gene editing strategy. The resulting BMPR2+/– lambs demonstrated cardiac and pulmonary vascular pathology that are consistent with BMPR2 mutation–driven PAH observed in humans. Given the genetic and physiological similarities of BMPR2+/– sheep to humans with heritable PAH, this large animal model will serve as a vital platform for mechanistic molecular studies and will provide a much-needed preclinical model for extensive treatment evaluations.
Authors
Sanjeev A. Datar, Nicholas Werry, Austin R. Brown, Devon S. Fitzpatrick, Oluwafemi Falade, Josephine F. Trott, Rachel Hutchings, Elena K. Amin, Jessica M. Morgan, Hythem Nawaytou, Gail H. Deutsch, Eric G. Johnson, Omar A. Gonzales Viera, Thomas F. Bishop, Tara Urbano Beach, Bret R. McNabb, Eric D. Austin, Jeffery R. Fineman, Alison L. Van Eenennaam
Total views: 2979
Abstract
BACKGROUND Elucidating immune signals through well-defined cohorts of pediatric acute pancreatitis (AP) and chronic pancreatitis (CP) patients is critical. This study aimed to evaluate plasma chemokine and cytokine levels in pediatric participants with CP, compared with AP and healthy controls (HCs), to identify unique biomarkers of CP.METHODS Individuals were identified from a prospectively collected pediatric cohort (n = 146). Immunoproteins (n = 247) were measured using the NULISAseq platform on samples from individuals with CP (n = 71), AP (n = 55), and HCs (n = 20).RESULTS The measured analytes showed separation among the 3 groups (R2 = 0.13, P < 0.001). In the CP group, TRANCE, TWEAK, FLT-1, HGF, and TRAIL were increased when compared with HC and AP patients (FDR-corrected P <0.05). A multivariable logistic regression model including all 5 proteins provided an AUC of 0.94 (0.93–0.96) for differentiating samples from CP versus AP or HC samples. In the AP group, CRP, IL-6, CD3E, ENRAGE, and MIF were elevated compared with HCs, while FGF-2, TAFA-5, IL-33, TRANCE, and CXCL12 were downregulated in the same acute time period (FDR-corrected P < 0.05). In the 21 patients with AP for whom follow-up samples were obtained, there was a notable decrease in sequential expression of IL-6 and CRP over 12 months and increased expression of CCL25, TAFA-5, and TRANCE proteins. Additionally, TRANCE was expressed on CP pancreatic tissue.CONCLUSIONS TRANCE was increased in pediatric patients with CP and decreased in those with AP during a flare. Future studies are needed to investigate the role of TRANCE and other analytes in the pathogenesis of CP.
Authors
Peter R. Farrell, Bomi Lee, Faizan Ahmed, Maria E. Moreno-Fernandez, Ajay Dixit, Juan Pablo Gurria, Nicholas J. Ollberding, Qing Duan, Vineet Garlapally, Phoebe Christian, Sohail Z. Husain, Maisam Abu-El-Haija
Total views: 2977
