Top read articles in the last 30 days
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Abstract
Acute myeloid leukemia (AML) is the most common adult leukemia diagnosis. Bone marrow (BM) niche significantly influences the initiation and progression of AML. However, our knowledge about the effect of leukemic niche on leukemia stem cells (LSC) and leukemogenesis is limited. In this study, we identified an extrinsic-regulatory function of latexin (Lxn) in leukemogenesis. Using a MLL-AF9–induced AML mouse model in WT and Lxn-KO (Lxn–/–) recipient mice, we found that Lxn deletion in the BM niche enhanced the survival of AML mice by suppressing LSCs and reducing blood blasts. Single-cell RNA-seq of stromal cells and cell communication analysis uncovered downregulation of the leukemia inhibitory factor receptor (LIFR) signaling pathway in the Lxn–/– niche, particularly within mesenchymal stromal cells (MSCs). Mechanistically, reduced LIFR level in Lxn–/– MSCs upregulated Cxcl9 expression, leading to increased recruitment of CD8 T cells and enhanced cytotoxicity against leukemic cells. Combination of Lxn niche deletion and immune checkpoint inhibitor PD-1 further prolonged survival. The findings have important clinical implications, suggesting that Lxn inhibition could improve the efficacy of AML therapies by targeting the leukemia niche and enhancing immune surveillance.
Authors
Cuiping Zhang, Xia Yao, Pinpin Sui, Liming Hou, Bowen Yan, Larry L. Luchsinger, Gang Huang, Sheng Tong, Youwen Zhang, Bojing Shao, Hong Qian, Hong Zheng, Hui Zhong, Feng-Chun Yang, Ying Liang
Total views: 4501
Abstract
Lineage plasticity, or transdifferentiation, is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition, or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, the mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multiomic profiling of TP53/RB1-loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon TP53/RB1 loss could be blocked through BET bromodomain inhibition. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single-agent treatment in suppressing growth of TP53/RB1-loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.
Authors
William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal
Total views: 4415
Abstract
Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying antifibrotic agents are currently available. We hypothesized that interferon regulatory factor 5 (IRF5) functions as a macrophage transcriptional regulator that directly transactivates matrix metalloproteinase 9 (MMP9) to initiate early extracellular matrix (ECM) remodeling. Analysis of 30 human obstructive nephropathy biopsy specimens demonstrated that IRF5+CD68+ macrophage density increased progressively with fibrosis severity and correlated significantly with α-smooth muscle actin–positive (α-SMA+) areas. In the murine unilateral ureteral obstruction (UUO) model, both global and myeloid-specific Irf5 deletion significantly attenuated collagen deposition, immune cell infiltration, and fibrotic gene expression compared with WT controls. Cleavage under targets and tagmentation (CUT&Tag) analysis demonstrated that IRF5 directly binds the Mmp9 enhancer region and increases chromatin accessibility. Consequently, myeloid-specific Irf5 KO significantly reduced Mmp9 mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, downregulated α-SMA and MMP9 expression, and reduced CD68+ macrophage infiltration. These findings identify the IRF5/MMP9 axis as a therapeutically targetable pathway driving macrophage-mediated ECM expansion and provide preclinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.
Authors
Jia Wei, Gengyu Du, Zixia Li, Min Yang, Ting Chen, Zihao Xu, Zhen Yuan, Yidan Zheng, Xiang Yan
Total views: 4403
Abstract
Endothelial progenitor cells (EPCs) are critical for vascular regeneration after injury. However, their role in pulmonary fibrosis (PF) remains unclear. Here, we identified a previously unrecognized population of lung capillary EPCs coexpressing c-KIT and FOXF1 (capEPCs) in adult human and mouse lungs. capEPCs were significantly reduced in lungs from patients with PF and in bleomycin-injured mice, implicating loss of this regenerative endothelial population in disease pathogenesis. Transplantation of donor capEPCs attenuated experimental PF, improved survival, reduced collagen deposition, and restored lung function. Donor capEPCs engrafted into the lung microcirculation of bleomycin-injured mice. Single-cell RNA sequencing identified interferon-induced transmembrane protein 3 as a highly enriched transcript in capEPCs. Conditioned media from IFITM3-overexpressing EPCs or recombinant IFITM3 enhanced endothelial proliferation and angiogenesis while suppressing TGF-β1–induced fibroblast activation in vitro. IFITM3 was found in capEPC-derived exosomes. Treatment with IFITM3-containing exosomes recapitulated the therapeutic effects of capEPC transplantation by improving endothelial function, inhibiting fibroblast activation, increasing animal survival, reducing lung fibrosis, and restoring lung function. Together these findings identified capEPC deficiency as a feature of PF and demonstrated that IFITM3-containing exosomes promoted vascular repair. Restoration of capEPC regenerative function or delivery of IFITM3-enriched exosomes may represent a promising therapeutic strategy for human PF.
Authors
Ying-Wei Lan, Jonathan Do, Wen Gao, Zicheng Deng, Xiaomei Xia, Enhong Li, Jillian Kash, Gautam Verma, Angara Sureshbabu, Kenneth S. Knox, Ross M. Bremner, Nicholas E. Banovich, Vladimir V. Kalinichenko, Tanya V. Kalin
Total views: 4322
Abstract
The mechanisms by which e-cigarette vaping (EV) affects lung health remain unclear. Clusters of EV-associated lung injury indicate that EV damages distal lung parenchyma and increases vulnerability to second-hit injury, including respiratory viral infections. Using human lung endothelial and epithelial cells and precision-cut lung slices, we investigated the mechanisms underlying distal lung cell injury and repair triggered by brief (24-hour) EV exposure. RNA-seq of lung tissue from golden Syrian hamsters evaluated the persistence of lung stress responses (10 days after 5 days of EV exposure) and the effect of EV on host defense against influenza A virus and SARS-CoV-2. EV disrupted the barrier function of human distal lung cells through JNK stress response signaling, triggered autophagy with impaired flux, suppressed mTOR signaling and cell proliferation, and culminated in apoptosis. Transcriptional responses in EV-exposed hamster lungs revealed persistent activation of JNK signaling, autophagy, barrier dysfunction, tissue remodeling, and impaired Th1 immunity. EV increased SARS-CoV-2 viral burden, downregulated antiviral genes (Ifit1, Isg15, Nfkbia), and amplified oxidative stress and IL-12 signaling. Short-term EV exposure triggered stress-induced distal lung cell injury with persistent changes in antiviral immunity and molecular pathways associated with tissue remodeling. That may increase susceptibility to viral infections and contribute to lung disease.
Authors
Tanner C. Rivera, Kelly S. Schweitzer, Christina Cornell, Jordan Nall, Nicholas Egersdorf, Courtney Moeder, Riley A. Cooney, Eszter K. Vladar, Steve D. Groshong, Gregory P. Downey, James P. Bridges, Richard Bowen, Hong Wei Chu, Irina Petrache
Total views: 4127
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: 4124
Abstract
Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer’s disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β–induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.
Authors
Yanting Chen, Khloud Ashraf Farouk Emam, Shuwen Yue, Jing Tian, Tienju Wang, Albert Park, Shalini Mishra, Gagan Deep, Zi-Jun Wang, Heng Du, Lan Guo
Total views: 4094
Abstract
Vascular plasticity is a crucial biological asset enabling our bodies to rapidly adapt to infections and acute inflammation. However, repeated insults during chronic disease can result in these vascular adaptations becoming irreversible, thereby driving disease progression and fibrosis. This study aimed to understand if phenotypic changes in endothelial cell (EC) identity could be indicative of progressive fibrosis and thereby offer diagnostic and therapeutic opportunities for patients with metabolic dysfunction–associated steatotic liver disease (MASLD). We integrated high-resolution imaging and proteomic and transcriptomic analysis, which collectively highlighted a central role for endothelial-mesenchymal transition–induced (EndMT-induced) EC plasticity in the derivation of fibrosis-associated EC (FAEC). We demonstrated that: (a) full-spectrum flow cytometry can provide new opportunities to categorize and phenotype EC subpopulations; (b) 2 distinct EndMT-derived FAEC subpopulations expanded during fibrogenesis (THY1.2+ICAM1+ and TAGLN+MCAM+ EC) that displayed unique immunomodulatory and metabolic phenotypes; (c) TAGLN+ FAEC are a conserved, profibrotic cell type that arose at early stages of MASLD; and (d) increased hepatic expression of TAGLN was significantly associated with detrimental patient outcomes at all stages of liver disease. This study paves the way for the development of FAEC-specific diagnostic and therapeutic approaches to tackle progressive fibrotic disease.
Authors
Christina Gkantsinikoudi, Joshua P. Dignam, Raju Kumar, Elliot Jokl, Meenakshi Rana, Wenhao Li, Maryna Samus, Stephanie Landi, Varinder S. Athwal, Timothy J. Kendall, Antal Rot, Jonathan A. Fallowfield, Karen Piper Hanley, William Alazawi, Neil P. Dufton
Total views: 3725
Abstract
Integrin αVβ3, a transmembrane receptor involved in tumor growth and metastasis, specifically recognizes and binds proteins with the Arg-Gly-Asp (RGD) peptide sequence. Using mRNA and/or protein expression data from 496 thyroid cancer (TC) samples in The Cancer Genome Atlas, 14 TC cell lines, and 70 TC and 10 normal thyroid tissues, we found that papillary TC exhibits the highest αVβ3 integrin expression. We then evaluated the therapeutic efficacy of a radiolabeled RGD analog, 177Lu-DOTA-EB-cRGDfK, in TC. Genetic knockout and overexpression of αVβ3 in TC cell lines confirmed the target specificity of 177Lu-DOTA-EB-cRGDfK. In mouse xenograft models established from human TC cell lines with high αVβ3 expression, 177Lu-DOTA-EB-cRGDfK demonstrated superior antitumor efficacy compared with standard-of-care lenvatinib and placebo. However, no synergistic benefit was observed with combination therapy. Biodistribution studies identified the kidneys as the dose-limiting organ. RNA-seq analysis of resected tumors demonstrated that 177Lu-DOTA-EB-cRGDfK induced a type I IFN response, characterized by upregulation of IFI6, IFIT1-2, and MX1, compared with both lenvatinib-treated tumors and placebo. These findings identify αVβ3 integrin as a promising therapeutic target in a subset of TCs and demonstrate that 177Lu-DOTA-EB-cRGDfK exhibits superior efficacy to lenvatinib, supporting its potential clinical translation for progressive TC refractory to standard therapies.
Authors
Sonam Kumari, Rhitajit Sarkar, Zhantong Wang, Shilpa Thakur, Laura Abaandou, Oksana Gavrilova, Huiyan Lu, Noha Behairy, Lixin Lang, Dale Kiesewetter, Vasyl Vasko, Joanna Klubo-Gwiezdzinska
Total views: 3656
Abstract
DNA ligase IV (LIGIV or LIG4) is essential for DNA double-strand break (DSB) repair. Hypomorphic LIG4 variants cause LIG4 syndrome, characterized by growth disturbance, increased radiosensitivity, predisposition to malignancies, adaptive immunodeficiency, and inflammatory conditions. Most of these manifestations are recapitulated in hypomorphic Lig4 mutant mice. However, no model mice with defective DSB repair have consistently exhibited inflammation. Here, we generated mutant mice carrying the LIG4 missense variant, p.W447C, found in a patient with LIG4 syndrome. Lig4W447C/W447C mice showed functional defects of LIGIV and manifested growth retardation, increased radiosensitivity, and life-threatening intestinal inflammation under severe adaptive immunodeficiency. The inflammation was dependent on lymphocytes and characterized by marked infiltration of Th1 cells and macrophages, along with elevated expression of IFN-γ–inducible genes. When Ifng was deleted, Th2 and Th17 instead of Th1 cells drove the inflammation. Single-cell RNA-seq analyses with TCR repertoire revealed that T cells from Lig4W447C/W447C mice preferentially used proximal Vα and Jα segments in V regions of TCRα chains and exhibited expansion of several clonotypes, a substantial portion of which were CD4+ T cells expressing IFN-γ. Thus, our hypomorphic Lig4 mutant mice represent a unique model for studying Th1-skewed intestinal inflammation under severe adaptive immunodeficiency.
Authors
Yusuke Yamashita, Hideki Kosako, Takashi Kato, Izumi Sasaki, Sadahiro Iwabuchi, Yuri Fukuda-Ohta, Tadashi Okamura, Misato Tane, Shotaro Tabata, Kazutaka Nakashima, Ken Tanaka, Kazunori Shiraishi, Yuki Uchihara, Daisuke Okuzaki, Kyoichi Isono, Atsushi Shibata, Tsunehiro Mizushima, Hiroaki Hemmi, Nobuo Kanazawa, Seiji Kodama, Hiroaki Miyoshi, Koichi Ohshima, Shinichi Hashimoto, Yoshio Fujitani, Takashi Sonoki, Shinobu Tamura, Tsuneyasu Kaisho
Total views: 3551
