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Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease
Graft-versus-Host disease is a major complication after allogeneic bone marrow transplantation and is ameliorated by adoptively transferred donor regulatory T cells. Here, the authors apply transcriptomic and TCR profiling to assess regulatory T cell organ-specific adaptation in murine bone marrow transplantation models.
- David J. Dittmar
- , Franziska Pielmeier
- & Michael Rehli
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Dermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice
The microbial community in the intestine can affect other organs such as the skin but it is not clear if the opposite can occur. Here the authors show that skin wounding affects the microbial composition of the intestinal flora which then enhances DSS induced colitis and intestinal inflammation.
- Tatsuya Dokoshi
- , Yang Chen
- & Richard L. Gallo
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Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Mechanisms regulating collagen clearance may be useful for treating fibrosis. Here, the authors conducted functional genome-wide screens and found that collagen biosynthesis directly regulates collagen clearance via a noncanonical function of SEL1L.
- Michael J. Podolsky
- , Benjamin Kheyfets
- & Kamran Atabai
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Vascular network-inspired fluidic system (VasFluidics) with spatially functionalizable membranous walls
Functional features in the spatiotemporal regulation of blood chemistry are not much explored. Here authors show vascular network-inspired fluidics, functionalizable for different region-specific trans-wall transport to regulate fluids over space and time.
- Yafeng Yu
- , Yi Pan
- & Ho Cheung Shum
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Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Hepatocytes regenerate the liver after injury, however, the tissue repair mechanisms have been little explored. Here, the authors show that midlobular and pericentral hepatocytes increase their number and size in response to chemical, physical, and viral insults facilitating liver regeneration.
- Inmaculada Ruz-Maldonado
- , John T. Gonzalez
- & Carlos Fernández-Hernando
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BACH1 controls hepatic insulin signaling and glucose homeostasis in mice
Hepatic insulin resistance plays a central role in metabolic syndrome. Here, the authors show that transcription factor BACH1 acts as a negative regulator of insulin signaling and that hepatic BACH1 deficiency ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or diabetic mice
- Jiayu Jin
- , Yunquan He
- & Dan Meng
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Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration
Alveolar epithelial progenitors in the lungs can regenerate the epithelial surface after acute injury. Here they generate lung organoids that can be used to study lung regeneration after injury and identify Nkx2-1 as a key regulator of alveolar progenitor activation.
- Andrea Toth
- , Paranthaman Kannan
- & William J. Zacharias
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TransformEHR: transformer-based encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records
Using AI to predict disease can improve interventions slow down or prevent disease. Here, the authors show that generative AI models built on the framework of Transformer, the model that also empowers ChatGPT, can achieve state-of-the-art performance on disease predictions based on longitudinal electronic records.
- Zhichao Yang
- , Avijit Mitra
- & Hong Yu
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Inferring bacterial transmission dynamics using deep sequencing genomic surveillance data
Studying rare genetic changes that arose as an infectious bacterium spread between lab mice, here the authors show that using the relative abundance of any changes rather than just whether they occurred can more precisely identify who likely infected who.
- Madikay Senghore
- , Hannah Read
- & Siouxsie Wiles
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A human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Acute exposure to radiation can lead to acute pneumonitis, fibrosis or death. Here the authors develop an alveolus-on chip model to study the molecular characteristics of radiation induced lung injury, better understand radiation induced lung disease and facilitate drug screening.
- Queeny Dasgupta
- , Amanda Jiang
- & Donald E. Ingber
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Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype
β-thalassemia is a prevalent genetic disorder causing severe anemia, with study of the underlying molecular defects impeded by paucity of suitable patient material. Here, the authors show that cellular model systems of βthalassemia can be used to identify new therapeutic targets and as screening platforms for new drugs and reagents.
- Deborah E. Daniels
- , Ivan Ferrer-Vicens
- & Jan Frayne
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Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis
Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue.
- Richard J. Hewitt
- , Franz Puttur
- & Clare M. Lloyd
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Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease
Pulmonary hypertension due to left heart disease is characterized by pulmonary arterial stiffening that results from extracellular matrix remodeling. Here, the authors show that elastin stabilization improves arterial biomechanics and attenuates pulmonary hypertension.
- Mariya M. Kucherenko
- , Pengchao Sang
- & Christoph Knosalla
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Longitudinal tracking of acute kidney injury reveals injury propagation along the nephron
The mechanisms of failed tubule repair after acute kidney injury are incompletely understood. Here, the authors show spatial and temporal analysis of cycling cells relative to initial necrosis and postulate pronounced injury expansion into non-necrotic tissue regions, predictive of tubule atrophy.
- Luca Bordoni
- , Anders M. Kristensen
- & Ina Maria Schiessl
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Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis
Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.
- Sofia Sirvent
- , Andres F. Vallejo
- & Marta E. Polak
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Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice
Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence, but the underlying mechanism remains poorly understood. Here, the authors show LAPTM5 expression ameliorates NASH and can potentially serve as a biological marker indicative of NASH progression.
- Lang Jiang
- , Jing Zhao
- & Jiahong Xia
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Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion
Plasmodium falciparum is known to secrete an aspartic protease called plasmepsin X. Here, Triglia et al present a characterisation of plasmepsin X function in the context of erythrocyte invasion and its regulation of PCRCR, a complex that anchors the leading vaccine candidate PfRh5 to the parasite surface.
- Tony Triglia
- , Stephen W. Scally
- & Alan F. Cowman
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Defective BVES-mediated feedback control of cAMP in muscular dystrophy
cAMP is an important second messenger involved in many aspects of biological processes. Here, Li et al. shows that blood vessel epicardial substance (BVES) is a negative regulator of cAMP signaling required for maintaining muscle mass and function.
- Haiwen Li
- , Peipei Wang
- & Renzhi Han
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Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis
Osteoclasts are derived from circulating myeloid cells to mediate bone repair, maintenance and remodeling. Here, the authors show that the lung also recruits and reprograms monocytes and alveolar macrophages into osteoclast-like cells to clear pathogenic particles from the airspace.
- Yasuaki Uehara
- , Yusuke Tanaka
- & Francis X. McCormack
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Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys
HIV infection results in the depletion of CD4+ T cells overtime and the loss of coordinated cellular immunity, but how this corresponds to the SIV infected African Green Monkey (AGM) model of non-progressive disease is not known. Here the authors assess the impact of experimental CD4+ T cell depletion in AGM and show that lack of disease progression and resistance to AIDS in this model are independent of CD4+ T cell loss.
- Quentin Le Hingrat
- , Paola Sette
- & Ivona Pandrea
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Altered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia
Raine syndrome is associated with loss-of-function mutations of FAM20C. Here we show that Raine-originated mutations abrogate the interaction between FAM20C and C4ST-1 to alter chondroitin sulfate sulfation status and impact biomineralization in vitro and bone mineral density in vivo in mouse models, thereby serving clues for Raine syndrome etiology.
- Toshiyasu Koike
- , Tadahisa Mikami
- & Hiroshi Kitagawa
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Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
The role of mitochondrial activity in angiogenesis is not entirely understood. Here, the authors show that mitochondria as a signaling hub and their dysfunction causes augmented TGFβ signaling to induce retinal sprouting retardation and vascular malformations.
- Haifeng Zhang
- , Busu Li
- & Jenny Huanjiao Zhou
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Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Here, authors show that Smad3 acetylation via HDAC6 inhibition reverses Duchenne muscular dystrophy-like symptoms in the mdx mouse model, suggesting a potential therapeutic target for the disorder.
- Alexis Osseni
- , Aymeric Ravel-Chapuis
- & Laurent Schaeffer
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2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Complex neuropathologies, like macular degeneration, are common but incompletely understood. Here the authors report a complex human retina pathology organoid model induced by HBEGF-TNF, causing PIEZO1-mediated photoreceptor degeneration by cell extrusion.
- Manuela Völkner
- , Felix Wagner
- & Mike O. Karl
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Phosphorylcholine-conjugated gold-molecular clusters improve signal for Lymph Node NIR-II fluorescence imaging in preclinical cancer models
Fluorescent tracers facilitate the identification and subsequent collection of tumour draining lymph node biopsies, enabling important clinical assessment. Here, the authors present a molecular gold nanocluster NIR-II fluorescent imaging probe and demonstrate its utility to visualise draining lymph nodes in breast and colon cancer mouse models.
- Ani Baghdasaryan
- , Feifei Wang
- & Hongjie Dai
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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome
Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo.
- Yuyao Tian
- , Wuming Wang
- & Wai-Yee Chan
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Comment
| Open AccessPaving the way to improve therapy for Myeloproliferative Neoplasms
Long-acting IFNα induces durable molecular responses in myeloproliferative neoplasms. Emerging studies, including Saleiro et al. recently published in Nature Communications, have identified promising candidates that may synergise with IFNα by targeting stem cell function or feedback loops that mediate treatment resistance.
- Megan Bywater
- & Steven W. Lane
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Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation
Lung transplantation is hindered by the scarcity of organs and by mortality following primary graft dysfunction. Here, the authors show that cytokine absorption can be used in donor lungs during ex vivo lung perfusion and post-transplant, and leads to restored lung function and reduced primary graft dysfunction in animal models.
- Haider Ghaidan
- , Martin Stenlo
- & Sandra Lindstedt
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Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder
Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.
- Elaine T. Lim
- , Yingleong Chan
- & George M. Church
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Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function
The miR-1/133/206 gene family codes for the most abundant microRNAs in striated muscles. Here, Klockner et al show that inactivation of all family members in skeletal muscle prevents formation of normal neuromuscular junctions due to increased expression of the adaptor protein CRK.
- Ina Klockner
- , Christian Schutt
- & Thomas Braun
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Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD.
- Clément Pontoizeau
- , Marcelo Simon-Sola
- & Manuel Schiff
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Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy
Inherited GPI deficiency (IGD) is caused by PIGO mutations. Here, the authors generate a mouse model of IGD and show that AAV-mediate gene therapy, for knock-in as well as extra-chromosomal expression of Pigo cDNA, ameliorates pathology in the mice.
- Ryoko Kuwayama
- , Keiichiro Suzuki
- & Yoshiko Murakami
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Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice
Treatments to rescue vision are currently limited. Here, the authors identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in humans. They also show that activating laterally projecting cells results improved vision in two mouse models of retinal degeneration.
- M. Rizzi
- , K. Powell
- & R. R. Ali
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Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation
Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology.
- Amanda C. Filiberto
- , Michael D. Spinosa
- & Ashish K. Sharma
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Skeletal muscle derived Musclin protects the heart during pathological overload
Cachexia is associated with poor prognosis in heart failure. Here the authors show that mice and patients with cardiac cachexia display reduced skeletal muscle expression and circulating levels of Musclin. Musclin ablation in skeletal muscle worsens, while its muscle-specific overexpression ameliorates heart failure in mice.
- Malgorzata Szaroszyk
- , Badder Kattih
- & Joerg Heineke
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Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.
- Ivana Slamova
- , Rozita Adib
- & J. Paul Simons
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Self-activating anti-infection implant
Bone implants with antibacterial and osteogenic properties are important for clinical applications, but creating both properties simultaneously remains challenging. Here, the authors demonstrate a self-activating implant using a hydroxyapatite and molybdenum disulfide coating which accelerates bone regeneration and at the same time prevents bacterial infection.
- Jieni Fu
- , Weidong Zhu
- & Shuilin Wu
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| Open Access
3D printed biomimetic cochleae and machine learning co-modelling provides clinical informatics for cochlear implant patients
Current spread hampers the efficacy of neuromodulation, while existing animal, in vitro and in silico models have failed to give patient-centric insights. Here the authors employ 3D printing and machine learning to advance clinical predictions of current spread for cochlear implant patients.
- Iek Man Lei
- , Chen Jiang
- & Yan Yan Shery Huang
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A human multi-lineage hepatic organoid model for liver fibrosis
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder which is associated with kidney and liver pathology, including liver fibrosis. Here the authors develop and characterize human liver organoids with a ARPKD mutation, and find that they show aspects of the pathology, including fibrosis.
- Yuan Guan
- , Annika Enejder
- & Gary Peltz
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Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy
Pancreatic tumors are frequently divided into basal and classical subtypes. Here, the authors use single cell sequencing to investigate organoids derived from pancreatic cancer tissue and find a hierarchy of distinct cell states, and classical and basal cells existing within the same tumor.
- Teresa G. Krieger
- , Solange Le Blanc
- & Christian Conrad
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| Open Access
Disrupting biological sensors of force promotes tissue regeneration in large organisms
Humans and other large mammals heal wounds by forming fibrotic scar tissue with diminished function. Here, the authors show that disrupting mechanotransduction through the focal adhesion kinase pathway in large animals accelerates healing, prevents fibrosis, and enhances skin regeneration.
- Kellen Chen
- , Sun Hyung Kwon
- & Geoffrey C. Gurtner
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A modular self-adjuvanting cancer vaccine combined with an oncolytic vaccine induces potent antitumor immunity
Successful cancer immune therapy correlates with a T cell-inflamed tumour microenvironment. Authors show here that co-administration of a self-adjuvanting protein vaccine and an antigen-expressing oncolytic virus in an optimised regimen strongly enhances T cell immunogenicity and may turn non-inflamed tumours proinflammatory and less resistant to checkpoint blockade therapy.
- Krishna Das
- , Elodie Belnoue
- & Guido Wollmann
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Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.
- Vidya C. Sinha
- , Amanda L. Rinkenbaugh
- & Helen Piwnica-Worms
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Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.
- Siddharth Menon
- , Ankit Salhotra
- & Natalina Quarto
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Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome
Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.
- Amanda M. Smith
- , Taylor A. LaValle
- & Timothy J. Ley
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| Open Access
STING suppresses bone cancer pain via immune and neuronal modulation
There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.
- Kaiyuan Wang
- , Christopher R. Donnelly
- & Ru-Rong Ji
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A pig BodyMap transcriptome reveals diverse tissue physiologies and evolutionary dynamics of transcription
A comprehensive transcriptomic survey of the pig could enable mechanistic understanding of tissue specialization and accelerate its use as a biomedical model. Here the authors characterize four distinct transcript types in 31 adult pig tissues to dissect their distinct structural and transcriptional features and uncover transcriptomic variability related to tissue physiology.
- Long Jin
- , Qianzi Tang
- & Mingzhou Li
FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation