491 results on '"Régénération"'
Search Results
2. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor
- Author
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Kadur Lakshminarasimha Murthy, Preetish, Sontake, Vishwaraj, Tata, Aleksandra, Kobayashi, Yoshihiko, Macadlo, Lauren, Okuda, Kenichi, Conchola, Ansley S, Nakano, Satoko, Gregory, Simon, Miller, Lisa A, Spence, Jason R, Engelhardt, John F, Boucher, Richard C, Rock, Jason R, Randell, Scott H, and Tata, Purushothama Rao
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Stem Cell Research ,Lung ,Respiratory ,Good Health and Well Being ,Alveolar Epithelial Cells ,Animals ,Cell Differentiation ,Cell Lineage ,Connectome ,Fibroblasts ,Gene Expression Profiling ,Humans ,Lung Diseases ,Mice ,Organoids ,Primates ,Regeneration ,Single-Cell Analysis ,Stem Cells ,General Science & Technology - Abstract
Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
- Published
- 2022
3. Human neural tube morphogenesis in vitro by geometric constraints
- Author
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Karzbrun, Eyal, Khankhel, Aimal H, Megale, Heitor C, Glasauer, Stella MK, Wyle, Yofiel, Britton, George, Warmflash, Aryeh, Kosik, Kenneth S, Siggia, Eric D, Shraiman, Boris I, and Streichan, Sebastian J
- Subjects
Biological Sciences ,Engineering ,Biomedical Engineering ,Regenerative Medicine ,Stem Cell Research - Embryonic - Human ,Stem Cell Research ,Pediatric ,Stem Cell Research - Nonembryonic - Human ,Neurosciences ,Biotechnology ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Ectoderm ,Humans ,Models ,Biological ,Morphogenesis ,Neural Plate ,Neural Tube ,Neural Tube Defects ,Organ Culture Techniques ,Regeneration ,Stem Cells ,General Science & Technology - Abstract
Understanding human organ formation is a scientific challenge with far-reaching medical implications1,2. Three-dimensional stem-cell cultures have provided insights into human cell differentiation3,4. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction5,6, neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients7. Our approach provides a new route to the study of human organ morphogenesis in health and disease.
- Published
- 2021
4. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
- Author
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Vogler, Thomas O, Wheeler, Joshua R, Nguyen, Eric D, Hughes, Michael P, Britson, Kyla A, Lester, Evan, Rao, Bhalchandra, Betta, Nicole Dalla, Whitney, Oscar N, Ewachiw, Theodore E, Gomes, Edward, Shorter, James, Lloyd, Thomas E, Eisenberg, David S, Taylor, J Paul, Johnson, Aaron M, Olwin, Bradley B, and Parker, Roy
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Brain Disorders ,Rare Diseases ,Genetics ,Biotechnology ,Dementia ,Acquired Cognitive Impairment ,Neurodegenerative ,Neurosciences ,Underpinning research ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Musculoskeletal ,Neurological ,Amyloid ,Amyotrophic Lateral Sclerosis ,Animals ,Cytoplasm ,DNA-Binding Proteins ,Female ,Humans ,Male ,Mice ,Models ,Biological ,Muscle Fibers ,Skeletal ,Muscle ,Skeletal ,RNA ,Messenger ,RNA-Binding Proteins ,Regeneration ,Sarcomeres ,TDP-43 Proteinopathies ,General Science & Technology - Abstract
A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
- Published
- 2018
5. Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
- Author
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Stewart KS, Abdusselamoglu MD, Tierney MT, Gola A, Hur YH, Gonzales KAU, Yuan S, Bonny AR, Yang Y, Infarinato NR, Cowley CJ, Levorse JM, Pasolli HA, Ghosh S, Rothlin CV, and Fuchs E
- Subjects
- Animals, Female, Male, Mice, Ligands, Phagocytes cytology, Phagocytes metabolism, Retinoids metabolism, Lipid Metabolism, Retinoic Acid Receptor gamma metabolism, Retinoid X Receptor alpha metabolism, Apoptosis, Hair Follicle cytology, Hair Follicle metabolism, Hair Follicle pathology, Homeostasis, Phagocytosis, Regeneration, Stem Cells cytology, Stem Cells metabolism
- Abstract
Billions of cells are eliminated daily from our bodies
1-4 . Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4 . How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche., (© 2024. The Author(s).)- Published
- 2024
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6. Tissues stay fit by balancing clearance of dying cells with regeneration.
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- 2024
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7. Modulation of tissue repair by regeneration enhancer elements
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Kang, Junsu, Hu, Jianxin, Karra, Ravi, Dickson, Amy L, Tornini, Valerie A, Nachtrab, Gregory, Gemberling, Matthew, Goldman, Joseph A, Black, Brian L, and Poss, Kenneth D
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Regenerative Medicine ,Genetics ,Acetylation ,Animal Fins ,Animals ,Animals ,Newborn ,Cell Proliferation ,Chromatin Assembly and Disassembly ,Enhancer Elements ,Genetic ,Epigenesis ,Genetic ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Heart ,Histones ,Leptin ,Lysine ,Male ,Mice ,Myocytes ,Cardiac ,Organ Specificity ,Promoter Regions ,Genetic ,Regeneration ,Transgenes ,Wound Healing ,Zebrafish ,Zebrafish Proteins ,General Science & Technology - Abstract
How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.
- Published
- 2016
8. Lens regeneration using endogenous stem cells with gain of visual function
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Lin, Haotian, Ouyang, Hong, Zhu, Jie, Huang, Shan, Liu, Zhenzhen, Chen, Shuyi, Cao, Guiqun, Li, Gen, Signer, Robert AJ, Xu, Yanxin, Chung, Christopher, Zhang, Ying, Lin, Danni, Patel, Sherrina, Wu, Frances, Cai, Huimin, Hou, Jiayi, Wen, Cindy, Jafari, Maryam, Liu, Xialin, Luo, Lixia, Zhu, Jin, Qiu, Austin, Hou, Rui, Chen, Baoxin, Chen, Jiangna, Granet, David, Heichel, Christopher, Shang, Fu, Li, Xuri, Krawczyk, Michal, Skowronska-Krawczyk, Dorota, Wang, Yujuan, Shi, William, Chen, Daniel, Zhong, Zheng, Zhong, Sheng, Zhang, Liangfang, Chen, Shaochen, Morrison, Sean J, Maas, Richard L, Zhang, Kang, and Liu, Yizhi
- Subjects
Medical Biotechnology ,Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Aging ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research - Nonembryonic - Non-Human ,Regenerative Medicine ,Eye Disease and Disorders of Vision ,Stem Cell Research ,Eye ,Animals ,Cataract ,Cataract Extraction ,Epithelial Cells ,Eye Proteins ,Homeodomain Proteins ,Homeostasis ,Humans ,Lens ,Crystalline ,Macaca ,PAX6 Transcription Factor ,Paired Box Transcription Factors ,Polycomb Repressive Complex 1 ,Proto-Oncogene Proteins ,Recovery of Function ,Regeneration ,Repressor Proteins ,Stem Cells ,Vision ,Ocular ,General Science & Technology - Abstract
The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.
- Published
- 2016
9. Reverse engineering spinal-cord injury.
- Published
- 2024
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10. Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.
- Author
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Lin B, Shah VS, Chernoff C, Sun J, Shipkovenska GG, Vinarsky V, Waghray A, Xu J, Leduc AD, Hintschich CA, Surve MV, Xu Y, Capen DE, Villoria J, Dou Z, Hariri LP, and Rajagopal J
- Subjects
- Animals, Female, Humans, Male, Mice, Metaplasia etiology, Metaplasia pathology, Tretinoin metabolism, Tretinoin pharmacology, Vitamin A metabolism, Vitamin A pharmacology, Lung Neoplasms etiology, Lung Neoplasms pathology, Mice, Inbred C57BL, Cell Plasticity, Epithelial Cells cytology, Epithelial Cells pathology, Regeneration, Respiratory Mucosa cytology, Respiratory Mucosa injuries, Respiratory Mucosa pathology, Stem Cells cytology
- Abstract
Airway hillocks are stratified epithelial structures of unknown function
1 . Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3 . Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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11. Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration.
- Author
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Peng, Tien, Frank, David B, Kadzik, Rachel S, Morley, Michael P, Rathi, Komal S, Wang, Tao, Zhou, Su, Cheng, Lan, Lu, Min Min, and Morrisey, Edward E
- Subjects
Lung ,Epithelial Cells ,Mesoderm ,Animals ,Mice ,Regeneration ,Wound Healing ,Paracrine Communication ,Cell Proliferation ,Down-Regulation ,Homeostasis ,Male ,Hedgehog Proteins ,Lung Injury ,Feedback ,Physiological ,Feedback ,Physiological ,General Science & Technology - Abstract
Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.
- Published
- 2015
12. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
- Author
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Wang, Bruce, Zhao, Ludan, Fish, Matt, Logan, Catriona Y, and Nusse, Roel
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Stem Cell Research ,Liver Disease ,Digestive Diseases ,1.1 Normal biological development and functioning ,Underpinning research ,Oral and gastrointestinal ,Animals ,Axin Protein ,Biomarkers ,Cell Lineage ,Cell Proliferation ,Clone Cells ,Diploidy ,Endothelial Cells ,Female ,Hepatocytes ,Homeostasis ,Liver ,Male ,Mice ,Polyploidy ,Regeneration ,Staining and Labeling ,Stem Cell Niche ,Stem Cells ,T-Box Domain Proteins ,Time Factors ,Veins ,Wnt Signaling Pathway ,General Science & Technology - Abstract
The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity.
- Published
- 2015
13. A gp130–Src–YAP module links inflammation to epithelial regeneration
- Author
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Taniguchi, Koji, Wu, Li-Wha, Grivennikov, Sergei I, de Jong, Petrus R, Lian, Ian, Yu, Fa-Xing, Wang, Kepeng, Ho, Samuel B, Boland, Brigid S, Chang, John T, Sandborn, William J, Hardiman, Gary, Raz, Eyal, Maehara, Yoshihiko, Yoshimura, Akihiko, Zucman-Rossi, Jessica, Guan, Kun-Liang, and Karin, Michael
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cancer ,Stem Cell Research - Nonembryonic - Non-Human ,Digestive Diseases ,Regenerative Medicine ,Stem Cell Research ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Adaptor Proteins ,Signal Transducing ,Animals ,Body Weight ,Cell Cycle Proteins ,Cell Differentiation ,Cell Proliferation ,Cytokine Receptor gp130 ,Disease Models ,Animal ,Enzyme Activation ,Epithelial Cells ,HEK293 Cells ,Homeostasis ,Humans ,Inflammation ,Inflammatory Bowel Diseases ,Intestinal Mucosa ,Mice ,Phosphoproteins ,Proto-Oncogene Proteins c-yes ,Proto-Oncogene Proteins pp60(c-src) ,Receptors ,Notch ,Regeneration ,Signal Transduction ,Up-Regulation ,YAP-Signaling Proteins ,General Science & Technology - Abstract
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
- Published
- 2015
14. Rat neurons repair mouse brains - and restore sense of smell.
- Author
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Reardon S
- Published
- 2024
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15. 'Mini liver' will grow in person's own lymph node in bold new trial.
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Kozlov M
- Published
- 2024
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16. Reversing blindness with stem cells.
- Author
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Savage, Neil
- Abstract
Regenerative therapies for the eyes could help to save vision in people with glaucoma, macular degeneration and damaged corneas. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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17. The promise and potential of stem cells in Parkinson’s disease.
- Author
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Gravitz, Lauren
- Abstract
Treatments that replace lost neurons and restore normal movement have entered clinical trials, but these therapies could offer more relief than cure. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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18. How stem cells could fix type 1 diabetes.
- Author
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Drew, Liam
- Abstract
Trials to replace the pancreatic β cells that are destroyed by this autoimmune disease are raising hopes of a cure. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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19. How organoids are advancing the understanding of chronic kidney disease.
- Author
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Bender, Eric
- Abstract
Although complete human kidneys grown from scratch are many years away, organoids built from pluripotent stem cells are already helping to model the condition and suggest better treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Sight restored by turning back the epigenetic clock.
- Author
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Huberman, Andrew D.
- Abstract
Neurons progressively deteriorate with age and lose resilience to injury. It emerges that treatment with three transcription factors can re-endow neurons in the mature eye with youthful characteristics and the capacity to regenerate. Resetting the methylation clock rejuvenates old retinal ganglion cells. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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21. Senescent cells damage the body throughout life.
- Author
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Glass, David J.
- Abstract
Cells in a state of arrested growth, called senescence, have been characterized in skeletal muscle in mice. Senescent cells promote inflammation and block regeneration, and thus might induce harmful changes in aged muscle. Muscle injury induces cell senescence, which promotes inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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22. Neurons that promote recovery from paralysis identified.
- Author
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Huang, Kee Wui and Azim, Eiman
- Abstract
Improved treatments for spinal-cord injury require both technological development and insights into the biology of recovery. High-resolution molecular maps of the nervous system are beginning to provide the latter. The biological mechanisms that underpin rehabilitation after paralysis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Pig organs partially revived in dead animals — researchers are stunned.
- Author
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Kozlov, Max
- Abstract
Scientists warn that the findings aren’t yet clinically relevant but say the research raises ethical questions about the definition of death. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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24. Macrophages provide a transient muscle stem cell niche via NAMPT secretion
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Carmen Sonntag, Laura A. Galvis, Phong D. Nguyen, Fernando J. Rossello, Jeroen Bakkers, Christophe Marcelle, Kelly L. Rogers, Verena C. Wimmer, Ziad Julier, Abdulsalam I. Isiaku, Thomas Boudier, Mikaël M. Martino, Dhanushika Ratnayake, Silke Berger, Jean Tan, Graham J. Lieschke, A.J. Wood, Peter D. Currie, Viola Oorschot, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
0301 basic medicine ,Male ,Nicotinamide phosphoribosyltransferase ,Inbred C57BL ,Myoblasts ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Single-cell analysis ,Receptors ,Myocyte ,Macrophage ,PAX7 Transcription Factor/metabolism ,RNA-Seq ,Stem Cell Niche ,Nicotinamide Phosphoribosyltransferase ,Zebrafish ,Receptors, CCR5/genetics ,Multidisciplinary ,PAX7 Transcription Factor ,Matrix Metalloproteinase 9/genetics ,Cell biology ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Skeletal/cytology ,030220 oncology & carcinogenesis ,Muscle ,Zebrafish/immunology ,Stem cell ,Single-Cell Analysis ,Regeneration/physiology ,Receptors, CCR5 ,Nicotinamide Phosphoribosyltransferase/genetics ,Biology ,03 medical and health sciences ,medicine ,Regeneration ,Animals ,Humans ,Progenitor cell ,Muscle, Skeletal ,Cell Proliferation ,Innate immune system ,Animal ,Macrophages ,Skeletal muscle ,Macrophages/cytology ,CCR5/genetics ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Muscle, Skeletal/cytology ,Disease Models ,Myoblasts/cytology - Abstract
Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.
- Published
- 2021
25. Control of osteoblast regeneration by a train of Erk activity waves
- Author
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Ben D. Cox, Kenneth D. Poss, Valerie A. Tornini, Alessandro De Simone, Julia Wang, Anna Chao, Maya N. Evanitsky, Stefano Di Talia, Luke Hayden, and Jianhong Ou
- Subjects
MAPK/ERK pathway ,Erk signalling ,Male ,Body Patterning ,MAP Kinase Signaling System ,Population ,Animal Scales ,Morphogenesis ,trigger waves ,tissue regeneration ,bone ,Article ,Diffusion ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Regeneration ,education ,Extracellular Signal-Regulated MAP Kinases ,Zebrafish ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,quantitative developmental biology ,Osteoblasts ,biology ,Chemistry ,Cell growth ,Regeneration (biology) ,Osteoblast ,live imaging ,biology.organism_classification ,zebrafish ,Cell biology ,medicine.anatomical_structure ,Female ,030217 neurology & neurosurgery - Abstract
Regeneration is a complex chain of events that restores a tissue to its original size and shape. The tissue-wide coordination of cellular dynamics that is needed for proper morphogenesis is challenged by the large dimensions of regenerating body parts. Feedback mechanisms in biochemical pathways can provide effective communication across great distances1–5, but how they might regulate growth during tissue regeneration is unresolved6,7. Here we report that rhythmic travelling waves of Erk activity control the growth of bone in time and space in regenerating zebrafish scales, millimetre-sized discs of protective body armour. We find that waves of Erk activity travel across the osteoblast population as expanding concentric rings that are broadcast from a central source, inducing ring-like patterns of tissue growth. Using a combination of theoretical and experimental analyses, we show that Erk activity propagates as excitable trigger waves that are able to traverse the entire scale in approximately two days and that the frequency of wave generation controls the rate of scale regeneration. Furthermore, the periodic induction of synchronous, tissue-wide activation of Erk in place of travelling waves impairs tissue growth, which indicates that wave-distributed Erk activation is key to regeneration. Our findings reveal trigger waves as a regulatory strategy to coordinate cell behaviour and instruct tissue form during regeneration. The rate of scale regeneration in zebrafish is controlled by the frequency of rhythmic travelling waves of Erk activity, which are broadcast from a central source to induce ring-like patterns of osteoblast tissue growth.
- Published
- 2021
26. Relocation sustains intestinal stem-cell numbers.
- Author
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Ellis, Stephanie J. and Fuchs, Elaine
- Abstract
A dynamic mode of stem-cell regulation has been discovered. Intestinal stem cells use migration to maintain a large pool of multifunctional cells, perhaps endowing the organ with robust responses to injury. An intestinal stem-cell pool is maintained through migration. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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27. Nerve regrowth can be painful.
- Author
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Cranfill, Suna L. and Luo, Wenqin
- Abstract
Neuronal fibres have been tracked as they regrow into the skin following nerve injury in mice. The analysis reveals that mis-wiring of pain-sensing fibres generates hypersensitivity to touch in skin associated with the injury. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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28. Supreme regenerative skills help sea spiders to regrow guts and more.
- Abstract
Other arthropods can regrow lost legs, but the sea spider can regenerate central organs all the way to the anus. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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29. Salamanders' regenerative potential might be driven by a specific protein variant.
- Published
- 2023
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30. Tissue-regeneration program underlies lung-cancer suppression.
- Published
- 2023
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31. p53 governs an AT1 differentiation programme in lung cancer suppression.
- Author
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Kaiser AM, Gatto A, Hanson KJ, Zhao RL, Raj N, Ozawa MG, Seoane JA, Bieging-Rolett KT, Wang M, Li I, Trope WL, Liou DZ, Shrager JB, Plevritis SK, Newman AM, Van Rechem C, and Attardi LD
- Subjects
- Animals, Mice, Mice, Knockout, Alleles, Gene Expression Profiling, Chromatin Assembly and Disassembly, DNA metabolism, Lung Injury genetics, Lung Injury metabolism, Lung Injury pathology, Disease Progression, Cell Lineage, Regeneration, Cell Self Renewal, Alveolar Epithelial Cells cytology, Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells pathology, Cell Differentiation, Lung cytology, Lung metabolism, Lung pathology, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lung Neoplasms prevention & control, Tumor Suppressor Protein p53 deficiency, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Lung cancer is the leading cause of cancer deaths worldwide
1 . Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1-4 , but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
- Full Text
- View/download PDF
32. Unlocking the secrets of scar-free skin healing.
- Author
-
Willyard, Cassandra
- Abstract
Skin regeneration is impeded by a host of factors. Working out the part played by each could lead to fresh approaches to treating burns and scars. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
33. Phenotypic landscape of intestinal organoid regeneration
- Author
-
Jeremy L. Jenkins, Katrin Volkmann, Shelly Meeusen, Prisca Liberali, Karyn Colman, Ludivine Challet Meylan, Michael B. Stadler, Ilya Lukonin, Janine E. Baaten, Denise Serra, Rui Zhao, and Francisca Maurer
- Subjects
Male ,0301 basic medicine ,Transcription, Genetic ,Receptors, Retinoic Acid ,Retinoic acid ,Tretinoin ,Biology ,Retinoid X receptor ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Organoid ,Animals ,Homeostasis ,Regeneration ,Intestinal Mucosa ,Vitamin A ,Multidisciplinary ,Sequence Analysis, RNA ,Cell Differentiation ,Phenotype ,Intestinal epithelium ,Cell biology ,Intestines ,Mice, Inbred C57BL ,Organoids ,Enterocytes ,030104 developmental biology ,Nuclear receptor ,chemistry ,030220 oncology & carcinogenesis ,Enterocyte differentiation ,Stem cell ,Signal Transduction - Abstract
The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.
- Published
- 2020
34. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration
- Author
-
Victoria Moiseeva, Andrés Cisneros, Valentina Sica, Oleg Deryagin, Yiwei Lai, Sascha Jung, Eva Andrés, Juan An, Jessica Segalés, Laura Ortet, Vera Lukesova, Giacomo Volpe, Alberto Benguria, Ana Dopazo, Salvador Aznar Benitah, Yasuteru Urano, Antonio del Sol, Miguel A. Esteban, Yasuyuki Ohkawa, Antonio L. Serrano, Eusebio Perdiguero, and Pura Muñoz-Cánoves
- Subjects
Inflammation ,Mice ,Aging ,Multidisciplinary ,Stem Cells ,Muscles ,Regeneration ,Humans ,Animals ,Senescence ,Muscle, Skeletal ,Cellular Senescence ,Aged - Abstract
Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life. We thank M. Jardí, A. Navarro, J. M. Ballestero, K. Slobodnyuk, M. González, J. López and M. Raya for their technical contributions; A. Harada and K. Tanaka for assistance in ATAC-seq; all of the members of the P.M.-C. laboratory for discussions; J. Campisi for p16-3MR mice; J. A. Fernández-Blanco (PRBB Animal Facility); O. Fornas (UPF/CRG FACS Facility); E. Rebollo (IBMB Molecular Imaging Platform); V. A. Raker for manuscript editing; and the members of the Myoage network (A. Maier) for human material. We acknowledge funding from MINECO-Spain (RTI2018-096068, to P.M.-C. and E.P.); ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, DPP-Spain, Fundació La MaratóTV3-80/19-202021 and MWRF to P.M.-C.; Fundació La MaratóTV3-137/38-202033 to A.L.S.; María-de-Maeztu Program for Units of Excellence to UPF (MDM-2014-0370) and Severo-Ochoa Program for Centers of Excellence to CNIC (SEV-2015-0505). This work was also supported by JST-CREST JPMJCR16G1 and MEXT/JSPS JP20H00456/18H05527 to Y.O.; the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502) to M.A.E.; V.M. and A.C. were supported by FPI and Maria-de-Maeztu predoctoral fellowships, respectively, and V.S. by a Marie Skłodowska-Curie individual fellowship. Parts of the figures were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licences/by/3.0/).
- Published
- 2021
35. Toes regrow with the help of these cells.
- Abstract
Cells at the base of the nail are key to regeneration of missing digit tips. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor
- Author
-
Preetish Kadur Lakshminarasimha Murthy, Vishwaraj Sontake, Aleksandra Tata, Yoshihiko Kobayashi, Lauren Macadlo, Kenichi Okuda, Ansley S. Conchola, Satoko Nakano, Simon Gregory, Lisa A. Miller, Jason R. Spence, John F. Engelhardt, Richard C. Boucher, Jason R. Rock, Scott H. Randell, and Purushothama Rao Tata
- Subjects
Lung Diseases ,Primates ,Multidisciplinary ,General Science & Technology ,Gene Expression Profiling ,Stem Cells ,Cell Differentiation ,Fibroblasts ,Stem Cell Research ,Article ,Organoids ,Mice ,Good Health and Well Being ,Alveolar Epithelial Cells ,Respiratory ,Connectome ,Animals ,Humans ,Regeneration ,Cell Lineage ,Single-Cell Analysis ,Lung - Abstract
Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
- Published
- 2021
37. Pioneering stem-cell trials in Japan report promising early results.
- Author
-
Mallapaty, Smriti
- Abstract
The country has invested hundreds of millions of dollars into research on induced pluripotent stem cells to treat diseased organs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
38. Stem cells: highlights from research.
- Author
-
King, Anthony
- Abstract
Self-organizing models of the early heart, why dead cells can be therapeutic, and other studies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
39. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.
- Author
-
Moiseeva V, Cisneros A, Sica V, Deryagin O, Lai Y, Jung S, Andrés E, An J, Segalés J, Ortet L, Lukesova V, Volpe G, Benguria A, Dopazo A, Benitah SA, Urano Y, Del Sol A, Esteban MA, Ohkawa Y, Serrano AL, Perdiguero E, and Muñoz-Cánoves P
- Subjects
- Aged, Animals, Humans, Mice, Stem Cells physiology, Fibrosis physiopathology, Transcriptome, Chromatin genetics, Geroscience, Aging metabolism, Aging physiology, Cellular Senescence physiology, Inflammation metabolism, Inflammation physiopathology, Muscle, Skeletal physiology, Muscle, Skeletal physiopathology, Regeneration, Stem Cell Niche physiology
- Abstract
Tissue regeneration requires coordination between resident stem cells and local niche cells
1,2 . Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4 ) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life., (© 2022. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
40. Plant-cell machinery for making metabolites transferred to mammalian cells.
- Published
- 2022
- Full Text
- View/download PDF
41. Regulation of intestinal immunity and tissue repair by enteric glia
- Author
-
Fränze, Progatzky, Michael, Shapiro, Song Hui, Chng, Bethania, Garcia-Cassani, Cajsa Helena, Classon, Selin, Sevgi, Anna, Laddach, Ana Carina, Bon-Frauches, Reena, Lasrado, Maryam, Rahim, Eleni-Maria, Amaniti, Stefan, Boeing, Kathleen, Shah, Lewis J, Entwistle, Alejandro, Suárez-Bonnet, Mark S, Wilson, Brigitta, Stockinger, and Vassilis, Pachnis
- Subjects
Inflammation ,Male ,Adventitia ,Nematospiroides dubius ,Duodenum ,Chemokine CXCL10 ,Intestines ,Interferon-gamma ,Mice ,Animals ,Homeostasis ,Humans ,Regeneration ,Female ,Gliosis ,Neuroglia ,Signal Transduction ,Strongylida Infections - Abstract
Tissue maintenance and repair depend on the integrated activity of multiple cell types
- Published
- 2020
42. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
- Author
-
Theodore Eugene Ewachiw, Joshua Wheeler, Michael P. Hughes, James Shorter, Edward Gomes, David Eisenberg, Oscar N. Whitney, Kyla A. Britson, Eric D. Nguyen, Thomas E. Lloyd, Aaron M. Johnson, Nicole Dalla Betta, Evan Lester, Bhalchandra S. Rao, Thomas O. Vogler, Bradley B. Olwin, J. Paul Taylor, and Roy Parker
- Subjects
0301 basic medicine ,Amyloid ,RNA-binding protein ,Protein aggregation ,TARDBP ,Sarcomere ,Article ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Regeneration ,Musculoskeletal System ,Multidisciplinary ,Chemistry ,Regeneration (biology) ,Skeletal muscle ,RNA ,nutritional and metabolic diseases ,3. Good health ,Cell biology ,nervous system diseases ,DNA-Binding Proteins ,030104 developmental biology ,medicine.anatomical_structure ,030217 neurology & neurosurgery - Abstract
A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
- Published
- 2018
43. Pancreas regeneration
- Author
-
Qiao Zhou and Douglas A. Melton
- Subjects
Pluripotent Stem Cells ,0301 basic medicine ,Multidisciplinary ,030209 endocrinology & metabolism ,Cellular Reprogramming ,Regenerative Medicine ,Adult Stem Cells ,Islets of Langerhans ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Animals ,Humans ,Regeneration ,Pancreas ,Cell Proliferation - Abstract
The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
- Published
- 2018
44. Whole-organism clone tracing using single-cell sequencing
- Author
-
Alexander van Oudenaarden, Anna Alemany, Josi Peterson-Maduro, Chloé S. Baron, Maria Florescu, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
Male ,0301 basic medicine ,Cell type ,Somatic cell ,Eye ,03 medical and health sciences ,Single-cell analysis ,Genes, Reporter ,Journal Article ,Animals ,Regeneration ,Cell Lineage ,Whole Body Imaging ,Progenitor cell ,General ,Zebrafish ,Embryonic Stem Cells ,Multidisciplinary ,biology ,Multipotent Stem Cells ,Brain ,Hematopoietic Stem Cells ,biology.organism_classification ,Research Highlight ,Embryonic stem cell ,Clone Cells ,Cell biology ,030104 developmental biology ,Single cell sequencing ,Cell Tracking ,Organ Specificity ,Animal Fins ,Female ,CRISPR-Cas Systems ,Single-Cell Analysis ,Transcriptome ,Clone (B-cell biology) ,Sequence Analysis - Abstract
Embryonic development is a crucial period in the life of a multicellular organism, during which limited sets of embryonic progenitors produce all cells in the adult body. Determining which fate these progenitors acquire in adult tissues requires the simultaneous measurement of clonal history and cell identity at single-cell resolution, which has been a major challenge. Clonal history has traditionally been investigated by microscopically tracking cells during development, monitoring the heritable expression of genetically encoded fluorescent proteins and, more recently, using next-generation sequencing technologies that exploit somatic mutations, microsatellite instability, transposon tagging, viral barcoding, CRISPR-Cas9 genome editing and Cre-loxP recombination. Single-cell transcriptomics provides a powerful platform for unbiased cell-type classification. Here we present ScarTrace, a single-cell sequencing strategy that enables the simultaneous quantification of clonal history and cell type for thousands of cells obtained from different organs of the adult zebrafish. Using ScarTrace, we show that a small set of multipotent embryonic progenitors generate all haematopoietic cells in the kidney marrow, and that many progenitors produce specific cell types in the eyes and brain. In addition, we study when embryonic progenitors commit to the left or right eye. ScarTrace reveals that epidermal and mesenchymal cells in the caudal fin arise from the same progenitors, and that osteoblast-restricted precursors can produce mesenchymal cells during regeneration. Furthermore, we identify resident immune cells in the fin with a distinct clonal origin from other blood cell types. We envision that similar approaches will have major applications in other experimental systems, in which the matching of embryonic clonal origin to adult cell type will ultimately allow reconstruction of how the adult body is built from a single cell.
- Published
- 2018
45. Biology’s beloved amphibian — the axolotl — is racing towards extinction
- Author
-
Erik Vance
- Subjects
Adult ,0106 biological sciences ,0301 basic medicine ,Amphibian ,Conservation of Natural Resources ,Thyroid Hormones ,Spinal dysraphism ,Population Dynamics ,Captivity ,Zoology ,Animals, Wild ,Extinction, Biological ,Regenerative Medicine ,History, 21st Century ,010603 evolutionary biology ,01 natural sciences ,Mice ,03 medical and health sciences ,Transforming Growth Factor beta ,Axolotl ,Animals, Laboratory ,biology.animal ,Animals ,Humans ,Regeneration ,Inbreeding ,Mexico ,Spinal Dysraphism ,Ecosystem ,Multidisciplinary ,Extinction ,biology ,History, 19th Century ,Gene Pool ,Genomics ,History, 20th Century ,biology.organism_classification ,Ambystoma mexicanum ,Lakes ,030104 developmental biology ,Habitat ,History, 16th Century ,Salamander ,Conservation biology - Abstract
Although abundant in captivity, the salamander has nearly disappeared from its natural habitat, and that’s a problem. Although abundant in captivity, the salamander has nearly disappeared from its natural habitat, and that’s a problem.
- Published
- 2017
46. Unlocking the secrets of scar-free skin healing
- Author
-
Cassandra Willyard
- Subjects
Keratinocytes ,Male ,0301 basic medicine ,Aging ,Benzylamines ,Scars ,Antlers ,Cyclams ,Regenerative Medicine ,Mice ,0302 clinical medicine ,Heterocyclic Compounds ,Skin Physiological Phenomena ,Adipocytes ,Skin ,Skin repair ,Multidisciplinary ,integumentary system ,Skin Transplantation ,030220 oncology & carcinogenesis ,Bone Morphogenetic Proteins ,Female ,medicine.symptom ,Burns ,Hair Follicle ,Reindeer ,Adult ,medicine.medical_specialty ,Cicatrix ,Young Adult ,03 medical and health sciences ,Fetus ,medicine ,Animals ,Humans ,Regeneration ,Surgery, Plastic ,Prenatal Injury ,Bioartificial Organ ,Skin, Artificial ,Wound Healing ,Bioartificial Organs ,business.industry ,Regeneration (biology) ,Fibroblasts ,Skin transplantation ,Dermatology ,Chemokine CXCL12 ,Disease Models, Animal ,030104 developmental biology ,Prenatal Injuries ,business - Abstract
Skin regeneration is impeded by a host of factors. Working out the part played by each could lead to fresh approaches to treating burns and scars. Skin regeneration is impeded by a host of factors. Working out the part played by each could lead to fresh approaches to treating burns and scars.
- Published
- 2018
47. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide
- Author
-
Alan Saghatelian, Jacqueline Fung, Emanuele Monteleone, Keiichi I. Nakayama, Pier Paolo Pandolfi, Akinobu Matsumoto, Alessandra Pasut, Riu Yamashita, Masaki Matsumoto, John G. Clohessy, Matsumoto, A., Pasut, A., Matsumoto, M., Yamashita, R., Fung, J., Monteleone, E., Saghatelian, A., Nakayama, K. I., Clohessy, J. G., and Pandolfi, P. P.
- Subjects
Male ,0301 basic medicine ,Endosomes ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Biological pathway ,Mice ,03 medical and health sciences ,Downregulation and upregulation ,Animals ,Humans ,Regeneration ,CRISPR ,Amino Acids ,Late endosome ,Adenosine Triphosphatases ,Gene Editing ,Genetics ,Multidisciplinary ,Muscles ,TOR Serine-Threonine Kinases ,HEK 293 cells ,RNA ,Cell biology ,Open reading frame ,HEK293 Cells ,030104 developmental biology ,Organ Specificity ,Multiprotein Complexes ,Knockout mouse ,RNA, Long Noncoding ,CRISPR-Cas Systems ,Lysosomes ,Peptides ,Signal Transduction - Abstract
Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide â small regulatory polypeptide of amino acid response' (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.
- Published
- 2016
48. Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals
- Author
-
K. Lenhard Rudolph, Julia von Maltzahn, Christian Feller, Johann M. Kraus, Beibei Xin, Simon Schwörer, Hans A. Kestler, André Lechel, Henriette Henze, Christy S. Varghese, Ali H. Baig, Ute Köber, Stefan Tümpel, Daniel B. Lipka, Kay L. Medina, Ruedi Aebersold, Remo Rohs, Francesco Neri, Manuel Schmidt, and Friedrich Becker
- Subjects
Male ,chromatin systems biology ,0301 basic medicine ,Senescence ,Aging ,Satellite Cells, Skeletal Muscle ,Physiological ,Cell ,Skeletal muscle ,Biology ,Stress ,Article ,Mice ,Hox genes ,03 medical and health sciences ,Genetic ,Stress, Physiological ,satellite cell ,medicine ,Animals ,Humans ,Epigenetics ,Muscle, Skeletal ,development ,Cellular Senescence ,Homeodomain Proteins ,Multidisciplinary ,histone modifications ,Chromatin ,Female ,Growth and Development ,Regeneration ,Epistasis, Genetic ,Muscles ,Stem Cells ,Wnt signaling pathway ,Skeletal ,Cell biology ,Satellite Cells ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,regeneration ,Epistasis ,Muscle ,Stem cell - Abstract
The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.
- Published
- 2016
49. Inhibition of LTβR signalling activates WNT-induced regeneration in lung
- Author
-
Zeynep Ertüz, Giorgi Beroshvili, Dominik Pfister, Adrien Guillot, Oliver Eickelberg, Mathias Heikenwalder, Eric Goffin, Reinoud Gosens, Gerald Burgstaller, Danijela Heide, Maximilian Strunz, Fabian J. Theis, Mareike Lehmann, Martin A. Lopez, Michael Boutros, Aicha Jeridi, Darcy E. Wagner, Yan Hu, Marlene Kohlhepp, Tracy O'Connor, Lore Becker, Frank Tacke, Thomas M. Conlon, Meshal Ansari, Indrabahadur Singh, Christoph Mayr, Martin Hrabé de Angelis, Tobias Stoeger, Emmanuel Dejardin, Hani N. Alsafadi, Melanie Königshoff, Sandra Prokosch, Chiara Ciminieri, Michael Dudek, Bernard Pirotte, Herbert B. Schiller, Johannes Beckers, Maja C. Funk, Percy A. Knolle, Martin Irmler, Stijn E. Verleden, Michael Lindner, Gizem Gunes, Rita Costa, Jenny Hetzer, Gerrit John-Schuster, Jakob Janzen, Ali Önder Yildirim, Groningen Research Institute for Asthma and COPD (GRIAC), Molecular Pharmacology, and Nanomedicine & Drug Targeting
- Subjects
0301 basic medicine ,Aging ,Apoptosis ,Adaptive Immunity ,Article ,03 medical and health sciences ,Mice ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Fibrosis ,Lymphotoxin beta Receptor ,Smoke ,medicine ,Animals ,Humans ,Regeneration ,Progenitor cell ,Lung ,beta Catenin ,Emphysema ,Multidisciplinary ,Innate immune system ,business.industry ,Regeneration (biology) ,Stem Cells ,Wnt signaling pathway ,NF-kappa B ,Acquired immune system ,medicine.disease ,Epithelium ,Immunity, Innate ,3. Good health ,Mice, Inbred C57BL ,Wnt Proteins ,030104 developmental biology ,Lymphotoxin ,medicine.anatomical_structure ,030228 respiratory system ,Alveolar Epithelial Cells ,Cancer research ,Female ,business ,Engineering sciences. Technology ,Signal Transduction - Abstract
Blockade of lymphotoxin beta-receptor (LT beta R) signalling restores WNT signalling and epithelial repair in a model of chronic obstructive pulmonary disease. Lymphotoxin beta-receptor (LT beta R) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures(1,2), which are associated with severe chronic inflammatory diseases that span several organ systems(3-6). How LT beta R signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LT beta R blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LT beta R ligands in adaptive and innate immune cells, enhanced non-canonical NF-kappa B signalling, and enriched LT beta R target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LT beta R signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LT beta R signalling dampened epithelial non-canonical activation of NF-kappa B, reduced TGF beta signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/beta-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LT beta R signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures(1) and inhibition of apoptosis with tissue-regenerative strategies.
- Published
- 2019
50. An organoid-based organ-repurposing approach to treat short bowel syndrome
- Author
-
Shinya, Sugimoto, Eiji, Kobayashi, Masayuki, Fujii, Yuki, Ohta, Kazuya, Arai, Mami, Matano, Keiko, Ishikawa, Kentaro, Miyamoto, Kohta, Toshimitsu, Sirirat, Takahashi, Kosaku, Nanki, Yoji, Hakamata, Takanori, Kanai, and Toshiro, Sato
- Subjects
Male ,Short Bowel Syndrome ,Colon ,Regenerative Medicine ,Rats ,Organoids ,Disease Models, Animal ,Organ Culture Techniques ,Ileum ,Rats, Inbred Lew ,Animals ,Heterografts ,Humans ,Regeneration ,Intestinal Mucosa - Abstract
The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro
- Published
- 2019
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