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| Open AccessHepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture
Hepatocytes dedifferentiate into progenitor-like cells in culture. Here, authors elucidate the dynamics and mechanisms of hepatocyte dedifferentiation and find an unexpected differentiation potential of hepatocytes into intestinal epithelial cells.
- Shizuka Miura
- , Kenichi Horisawa
- & Atsushi Suzuki
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Article
| Open AccessMapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth
Human hepatocytes remain hard to grow in vitro. Here, the authors temporally map the early stages of organoid growth initiated from fetal and adult hepatocytes, leveraging this knowledge to design maturation and improved expansion conditions.
- Delilah Hendriks
- , Benedetta Artegiani
- & Hans Clevers
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Article
| Open AccessIlluminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans
The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.
- Joakim Lehrstrand
- , Wayne I. L. Davies
- & Ulf Ahlgren
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Article
| Open AccessMyosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads
Myosin-binding protein C (MyBP-C) resides and interacts with the myosin filaments in striated muscle and regulates contraction via an unclear mechanism. Here, the authors demonstrate that MyBP-C regulates the performance of myosin heads.
- Anthony L. Hessel
- , Nichlas M. Engels
- & Samantha P. Harris
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Article
| Open AccessHeterozygous missense variant in GLI2 impairs human endocrine pancreas development
Mutations in the Hedgehog signaling have not been previously associated to diabetes. Here, authors identify a missense variant of GLI2 in a family with early-onset diabetes and report an essential role of this gene during human iPSC-based pancreatic differentiation.
- Laura M. Mueller
- , Abigail Isaacson
- & Francesca M. Spagnoli
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Article
| Open AccessDecomposing cortical activity through neuronal tracing connectome-eigenmodes in marmosets
The relationship between neuroanatomical connections and functional activity is still unclear. Using graph signal processing, the authors show neuronal tracing connectome eigenmodes constrain cortical activity in marmosets.
- Jie Xia
- , Cirong Liu
- & Wei Liao
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Article
| Open AccessCellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Upon physiological injury, hepatocytes transdifferentiate into biliary epithelial cells, a process involving molecular rewiring. Here, authors show that Sox4 organizes the early steps, acting as a pioneer factor to decommission hepatocyte enhancers and open chromatin around biliary genes.
- Takeshi Katsuda
- , Jonathan H. Sussman
- & Ben Z. Stanger
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Comment
| Open AccessThe bioethics of skeletal anatomy collections from India
Millions of skeletal remains from South Asia were exported in red markets (the underground economy of human tissues/organs) to educational institutions globally for over a century. It is time to recognize the personhood of the people who were systematically made into anatomical objects and acknowledge the scientific racism in creating and continuing to use them.
- Sabrina C. Agarwal
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Article
| Open AccessArticular surface interactions distinguish dinosaurian locomotor joint poses
Criteria for evaluating joint articulation in vertebrates are lacking. Here, the authors propose an approach for combining measurements of 3D articular overlap, symmetry, and congruence into a single metric, and apply this to examine the walking stride of Deinonychus antirrhopus.
- Armita R. Manafzadeh
- , Stephen M. Gatesy
- & Bhart-Anjan S. Bhullar
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Article
| Open AccessNeonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment
Neonatal brain dynamics are not well understood. Here, the authors characterise brain transient states in neonates, and show that preterm infants display altered whole brain dynamics and an atypical repertoire of regional transient states, which are associated with behavioural outcomes at 18 months of age.
- Lucas G. S. França
- , Judit Ciarrusta
- & Dafnis Batalle
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Article
| Open AccessCDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver
Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.
- Alexander J. Hu
- , Wei Li
- & Miaofen G. Hu
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Article
| Open AccessBrain asymmetries from mid- to late life and hemispheric brain age
The human brain is highly asymmetrical and increasingly so with age. Here the authors examine hemispheric brain age estimates, which provide additional insights into brain asymmetries.
- Max Korbmacher
- , Dennis van der Meer
- & Ivan I. Maximov
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Article
| Open AccessStructural connectome architecture shapes the maturation of cortical morphology from childhood to adolescence
Cortical morphology shows maturation during childhood and adolescence. Here the authors show this is structurally constrained by a diffusion network model and that this constraint is linked to gene expression profiles of microstructural development.
- Xinyuan Liang
- , Lianglong Sun
- & Yong He
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Article
| Open AccessSegment anything in medical images
Segmentation is an important fundamental task in medical image analysis. Here the authors show a deep learning model for efficient and accurate segmentation across a wide range of medical image modalities and anatomies.
- Jun Ma
- , Yuting He
- & Bo Wang
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Article
| Open AccessApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis
Lipolysis in adipose tissue releases fatty acids during fasting. Here, authors show that ApoL6, a lipid droplet-associated protein, is specifically expressed in adipocytes upon feeding to inhibit lipolysis by directly interacting with Perilipin 1 to competitively inhibit Perilipin 1-HSL interaction.
- Yuhui Wang
- , Hai P. Nguyen
- & Hei S. Sul
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Article
| Open AccessMegakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Circulating cell-free DNA (cfDNA) has diagnostic potential, and clarifying its origins will aid in the minimally-invasive detection and monitoring of disease. Here, authors find that physiologically, megakaryocytes are major sources of cfDNA, while erythroblasts also release small amounts of cfDNA.
- Joshua Moss
- , Roni Ben-Ami
- & Yuval Dor
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Article
| Open AccessReprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice
Skeletal muscle’s metabolic status has an impact on health and the prognosis of chronic diseases. Here the authors unveil an atlas of open chromatin regions in skeletal muscles using single-nucleus techniques on juvenile male mice, highlight regulatory dynamics between normal and denervated states, and pinpoint ELK4 as a pivotal factor in muscle atrophy.
- Hongchun Lin
- , Hui Peng
- & Zhaoyong Hu
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Article
| Open AccessA human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.
- Fabian Wirth
- , Fabrice D. Heitz
- & Jan Grimm
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Article
| Open AccessA phylogenetically-conserved axis of thalamocortical connectivity in the human brain
The principles underpinning the projection patterns of the thalamus to the cortex are not well characterised. Here, the authors reveal a medial to lateral thalamic gradient of genetic and connectomic variation which aligns with an anterior to posterior cortical pattern.
- Stuart Oldham
- & Gareth Ball
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Matters Arising
| Open AccessFluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base
- Shinji Naganawa
- , Yutaka Kato
- & Michihiko Sone
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Article
| Open AccessBone marrow adiposity modulation after long duration spaceflight in astronauts
Bone marrow adiposity is linked to disease, and it is unknown how it is modulated during space travel. Here, the authors show that astronauts returning from ISS missions had decreased marrow fat and increased hematopoiesis and bone formation, suggesting that adipose reserves in the bone marrow might be used as an energy source to counteract anemia and bone loss associated with space flight.
- Tammy Liu
- , Gerd Melkus
- & Guy Trudel
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Article
| Open AccessA spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease
Kidney stone disease causes significant morbidity and increases in health care utilization. Here, the authors define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human renal papilla and identify associated urinary biomarkers.
- Victor Hugo Canela
- , William S. Bowen
- & Tarek M. El-Achkar
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Article
| Open AccessHighly efficient platelet generation in lung vasculature reproduced by microfluidics
Highly efficient generation of platelets in the vasculature. Here, Zhao et al. show that the mouse platelet precursor cell, megakaryocytes, generate physiological numbers of functional platelets when passaged repeatedly through pulmonary vasculature.
- Xiaojuan Zhao
- , Dominic Alibhai
- & Alastair W. Poole
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Article
| Open AccessEarly presence of Homo sapiens in Southeast Asia by 86–68 kyr at Tam Pà Ling, Northern Laos
Here the authors report new human fossils from Tam Pà Ling cave, Laos, consisting of a cranial and a tibial fragment, dated to 68–86 thousand years ago. This find confirms that Homo sapiens were present in Southeast Asia by this time and the shape of the fossils indicates they may have descended from non-local populations.
- Sarah E. Freidline
- , Kira E. Westaway
- & Fabrice Demeter
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Article
| Open AccessAugmented temperature fluctuation aggravates muscular atrophy through the gut microbiota
Higher diurnal temperature range in humans correlates with the prevalence of sarcopenia. Here, the authors show that fluctuated temperature exposure accelerates muscle atrophy and dampens exercise performance via altering microbiota composition in aged mice.
- Ya Liu
- , Yifan Guo
- & Yan Huang
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Article
| Open AccessRare genetic variants impact muscle strength
Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.
- Yunfeng Huang
- , Dora Bodnar
- & Heiko Runz
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Article
| Open AccessTransparent tissue in solid state for solvent-free and antifade 3D imaging
Current liquid-based optical clearing protocols can suffer from solvent evaporation and photobleaching. Here, the authors develop a solid high-refractive-index polymer to embed mouse and human tissues for clearing and antifade high-resolution 3D imaging.
- Fu-Ting Hsiao
- , Hung-Jen Chien
- & Shiue-Cheng Tang
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Article
| Open AccessVagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice
Coagulation factor VIII deficiency in hemophilia A disrupts clotting and prolongs bleeding. Here, the authors show that vagus nerve stimulation bypasses this defect and improves hemostasis in hemophilia A mice through a mechanism requiring acetylcholine-secreting ChAT+ T lymphocytes in spleen and α7nAChR on circulating platelets.
- Carlos E. Bravo-Iñiguez
- , Jason R. Fritz
- & Jared M. Huston
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Article
| Open AccessDirectionality of developing skeletal muscles is set by mechanical forces
The mechanisms that drive myocyte orientation and fusion to control muscle directionality are not well understood. Here authors show that the developing skeleton produces mechanical tension that instructs the directional outgrowth of skeletal muscles.
- Kazunori Sunadome
- , Alek G. Erickson
- & Igor Adameyko
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Article
| Open AccessAnatomical and functional maturation of the mid-gestation human enteric nervous system
Dershowitz and colleagues assess second trimester human fetal enteric nervous system development and function. They describe structural reorganization of the enteric nervous system that corresponds to gastrointestinal motility onset in ex vivo preparations.
- Lori B. Dershowitz
- , Li Li
- & Julia A. Kaltschmidt
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Article
| Open AccessDefective 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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Article
| Open AccessSOX17-positive rete testis epithelium is required for Sertoli valve formation and normal spermiogenesis in the male mouse
A valve-like structure called this Sertoli valve (SV) supports spermatogenesis by modulating the directional fluid flow in mouse testis. The SV formation is supported by its neighboring SOX17 + rete testis (RT). This study highlights the essential roles of RT and SV in spermatogenesis.
- Aya Uchida
- , Kenya Imaimatsu
- & Yoshiakira Kanai
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Article
| Open AccessExceptional preservation and foot structure reveal ecological transitions and lifestyles of early theropod flyers
The shape of bird toe pads and foot scales can be used to infer their behaviour. Here, the authors examine fossil evidence of toe pads and scales, in addition to claws and bones, from birds and close relatives, illustrating diverse lifestyles and ecological roles among early theropod flyers.
- Michael Pittman
- , Phil R. Bell
- & Thomas G. Kaye
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Article
| Open AccessAdipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects
Although thyroid hormone (TH) has anti-obesity potential, systemic administration of TH causes severe adverse effects without obvious weight loss. Here, the authors show that adipose tissue-targeted delivery of TH with liposomes is a safe and efficient strategy to treat obesity and its related complications in mice.
- Kang Chen
- , Lai Yee Cheong
- & Aimin Xu
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Article
| Open AccessMuscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice
The group of Shih-Yin Tsai observed age-associated neuromuscular junction structural instability in male but not female mice which is driven by dysregulation of mTOR complex 1 activity. Genetic activation of the downstream phosphorylation target 4EBP1 in the muscle remodeled the neuromuscular junction and enhanced synaptic transmission.
- Seok-Ting J. Ang
- , Elisa M. Crombie
- & Shih-Yin Tsai
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Article
| Open AccessBiasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration
Myoblast fusion is essential for development of multinucleated myofibers. Here, the authors show that ablation of Elmo 1 and Elmo2 impairs myoblast fusion in mice, and that expression of an open conformation of Elmo2 promotes muscle regeneration and improves the phenotype of Dysferlin-null dystrophic mice.
- Viviane Tran
- , Sarah Nahlé
- & Jean-François Côté
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Article
| Open AccessDifferential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy
Dynamin 2 is a large GTPase linked to several human diseases. Here, Gómez-Oca et al. investigate the functions of muscle dynamin 2 isoforms and provide insights into their differential implication in centronuclear myopathy pathogenesis and treatment.
- Raquel Gómez-Oca
- , Evelina Edelweiss
- & Jocelyn Laporte
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Article
| Open AccessIntestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost
The role of lifespan-regulating protein expression in specific tissues in C. elegans is murky. Here, the authors provide clarity by inducible degradation of longevity-related proteins, demonstrating that intestinal DAF-2 is a major determinant of lifespan in the worm.
- Yan-Ping Zhang
- , Wen-Hong Zhang
- & Meng-Qiu Dong
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Article
| Open AccessCryogenic contrast-enhanced microCT enables nondestructive 3D quantitative histopathology of soft biological tissues
The authors present cryogenic contrast-enhanced MicroCT (cryo-CECT), which by freezing stained samples at optimal freezing rates improves the visualization of the tissue microstructure. They demonstrate quantitative 3D analysis of individual tissue constituents, such as muscle and collagen fibers.
- Arne Maes
- , Camille Pestiaux
- & Greet Kerckhofs
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Article
| Open AccessThe Hippo pathway links adipocyte plasticity to adipose tissue fibrosis
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
- Hongyu Shen
- , Xun Huang
- & Yifu Qiu
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Article
| Open AccessMitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles
How different physical configurations between sarcomeres and mitochondria alter energetic support for contractile function of skeletal muscle is not clear. Here the authors use advanced 3D imaging and analysis techniques to show how space is made for mitochondria within the tightly packed sarcomere networks of striated muscle cells.
- Prasanna Katti
- , Alexander S. Hall
- & Brian Glancy
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Article
| Open AccessBeiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
- Yusuke Adachi
- , Kazutaka Ueda
- & Issei Komuro
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Article
| Open AccessBiliary NIK promotes ductular reaction and liver injury and fibrosis in mice
Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
- Zhiguo Zhang
- , Xiao Zhong
- & Liangyou Rui
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Article
| Open AccessSpatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis
The mechanisms that govern cell fate decisions of postmigratory cranial neural crest cells remain largely unknown. Here the authors present a spatiotemporal single-cell regulatory atlas tracking these cells’ dental lineage diversification.
- Junjun Jing
- , Jifan Feng
- & Yang Chai
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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Article
| Open AccessOsteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
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Review Article
| Open AccessIdentification, discrimination and heterogeneity of fibroblasts
In this review, the authors look at how recent progress in single-cell transcriptomics complement and enrich the classical, largely morphological, portraits of fibroblasts. The detailed molecular information now available provides new insights into fibroblast identity, heterogeneity and function.
- Urban Lendahl
- , Lars Muhl
- & Christer Betsholtz
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Article
| Open AccessDepletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy
Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies.
- Justin G. Boyer
- , Jiuzhou Huo
- & Jeffery D. Molkentin
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Article
| Open AccessOrigins of direction selectivity in the primate retina
Neural coding for motion direction has been studied intensively in the visual cortex of non-human primates. Here, the authors establish an origin for direction selectivity in the retina of the macaque monkey.
- Yeon Jin Kim
- , Beth B. Peterson
- & Dennis M. Dacey