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| Open AccessTranslational control by DHX36 binding to 5′UTR G-quadruplex is essential for muscle stem-cell regenerative functions
Skeletal muscle stem cells (or satellite cells, SCs) are normally quiescent but activate and expand in response to injury. Here the authors show that induction of DHX36 helicase during SC activation promotes mRNA translation by binding to 5′UTR mRNA G-quadruplexes (rG4) in targets including Gnai2 and unwinding them.
- Xiaona Chen
- , Jie Yuan
- & Huating Wang
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Article
| Open AccessChromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.
- Chi Zhang
- , Filippo Macchi
- & Kirsten C. Sadler
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Article
| Open AccessHIRA stabilizes skeletal muscle lineage identity
The epigenetic mechanisms coordinating the maintenance of adult cellular lineages remain poorly understood. Here the authors demonstrate that HIRA, a H3.3 histone chaperone, establishes the chromatin landscape required for skeletal muscle cell identity.
- Joana Esteves de Lima
- , Reem Bou Akar
- & Frédéric Relaix
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Article
| Open AccessReinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.
- Christos Karampelias
- , Habib Rezanejad
- & Olov Andersson
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Article
| Open AccessHuman stem cells harboring a suicide gene improve the safety and standardisation of neural transplants in Parkinsonian rats
Stem cell grafts present a risk of tissue overgrowth/tumors. Here, the authors utilise a human pluripotent stem cell line carrying a FailSafe suicide gene to not only ablate proliferative cells, but through timely gene activation, improve the purity of neural grafts in Parkinsonian rats.
- Isabelle R. de Luzy
- , Kevin C. L. Law
- & Clare L. Parish
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Article
| Open AccessSmall-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues
Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.
- Nathaniel Kastan
- , Ksenia Gnedeva
- & A. J. Hudspeth
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Article
| Open AccessSox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors
How endothelial to mesenchymal transition is regulated in endovascular progenitors is unclear. Here, the authors show that blocking Sox9 expression in murine endovascular progenitors regulates this transition on skin wounding, affecting the size of scarring, with changes in Rbpj having the opposite effect.
- Jilai Zhao
- , Jatin Patel
- & Kiarash Khosrotehrani
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Article
| Open AccessSingle-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Epidermal cultures can treat skin diseases, such as Junctional Epidermolysis Bullosa, but the signature of stem cells is unclear. By single cell RNAseq analyses on human keratinocytes, the authors identify the molecular profile of holoclones and the role of FOXM1 in regulating the proliferative potential of epidermal stem cells.
- Elena Enzo
- , Alessia Secone Seconetti
- & Michele De Luca
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Article
| Open AccessFunctional regeneration and repair of tendons using biomimetic scaffolds loaded with recombinant periostin
The regeneration of functional tendons remains a clinical challenge. Here the authors develop a biomimetic scaffold loaded with recombinant periostin and demonstrate its functionality in promoting tendon stem/progenitor cell recruitment and tenogenic differentiation, and tendon regeneration in a rat full-cut Achilles tendon defect model.
- Yu Wang
- , Shanshan Jin
- & Yan Liu
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Article
| Open AccessReconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds
The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.
- Sara Campinoti
- , Asllan Gjinovci
- & Paola Bonfanti
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Article
| Open AccessDirect reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells
The conditions to induce human hepatic progenitor cells from other cell types are unclear. Here, the authors reprogram human endothelial cells to hepatic progenitor cells by expressing FOXA3, HNF1A and HNF6, capable of giving rise to hepatocytes and cholangiocytes that reconstitute damaged liver tissues on transplantation.
- Hiroki Inada
- , Miyako Udono
- & Atsushi Suzuki
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Article
| Open AccessIL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration
Signaling of IL-33 via its receptor, ST2, has been implicated in macrophage function in tissue repair. Here the authors show, using genetic mouse models and single-cell transcriptomic data, that the IL-33/ST2 axis regulates both ILC2-derived IL-13 and macrophage differentiation/reparative function required for club cell regeneration.
- Rania Dagher
- , Alan M. Copenhaver
- & Marina Pretolani
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Article
| Open AccessIntegrin-alpha-6+ Candidate stem cells are responsible for whole body regeneration in the invertebrate chordate Botrylloides diegensis
Clonal ascidians are able to undergo whole body regeneration (WBR), where entire new bodies can be regenerated from blood vessel fragments. Here, the authors provide evidence in Botrylloides diegensis supporting pou3 and vasa expressing blood-borne cells isolated with anti-IA6 antibody as candidate stem cells responsible for WBR.
- Susannah H. Kassmer
- , Adam D. Langenbacher
- & Anthony W. De Tomaso
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Article
| Open AccessBidirectional Wnt signaling between endoderm and mesoderm confers tracheal identity in mouse and human cells
How murine tracheal mesenchyme is specified during development is unclear. Here, the authors show a Wnt pathway target, Tbx4, is needed but this is regulated by Wnt signals from neighbouring tracheal epithelial cells, and take advantage of this knowledge to generate tracheal cartilage and smooth muscle on dish from mouse and human embryonic stem cells.
- Keishi Kishimoto
- , Kana T. Furukawa
- & Mitsuru Morimoto
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Article
| Open AccessInhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury
Chronic inflammation is a feature of age-related regenerative decline in skeletal muscles, but how it directly affects resident muscle stem cell fate and function is unclear. Here, the authors show that Ccr2 signaling in muscle stem cell derived progenitors represses terminal myogenic differentiation, and that targeting Ccr2 on aged myogenic progenitors rejuvenates aged skeletal muscle healing and function.
- Roméo S. Blanc
- , Jacob G. Kallenbach
- & Joe V. Chakkalakal
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Article
| Open AccessAlveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis
Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis.
- Maximilian Strunz
- , Lukas M. Simon
- & Herbert B. Schiller
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Article
| Open AccessLong-term culture of human pancreatic slices as a model to study real-time islet regeneration
The ability to culture live pancreatic tissue slices for long periods of time would enable longitudinal studies ex vivo. Here the authors culture human and mouse pancreatic slices in a perfluorocarbon-based culture system and show stable endocrine and exocrine function for up to ten days in culture.
- Mirza Muhammad Fahd Qadir
- , Silvia Álvarez-Cubela
- & Juan Domínguez-Bendala
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| Open AccessLong noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly
Long noncoding RNA SAM (Sugt1 associated muscle) is upregulated in the proliferating myoblast cells. Here the authors investigate SAM knockout mice and suggest that SAM binds and stabilizes Sugt1, a co-chaperone protein that regulates kinetochore assembly.
- Yuying Li
- , Jie Yuan
- & Huating Wang
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Article
| Open AccessGenome and single-cell RNA-sequencing of the earthworm Eisenia andrei identifies cellular mechanisms underlying regeneration
The mechanisms regulating regeneration of the earthworm are unclear. Here, the authors use genomic and transcriptomic analysis of the earthworm Eisenia andrei together with Hi-C analysis to identify genes involved and show activation of LINE2 transposable elements on regeneration.
- Yong Shao
- , Xiao-Bo Wang
- & Dong-Dong Wu
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Article
| Open AccessTFEB regulates murine liver cell fate during development and regeneration
The Transcription Factor EB (TFEB) is known to regulate cellular homeostasis and energy metabolism, but its role in cell fate determination in the liver is unknown. Here, the authors show that TFEB regulates the progenitor/cholangiocyte lineage and that its depletion prevents tissue recovery upon injury.
- Nunzia Pastore
- , Tuong Huynh
- & Andrea Ballabio
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Article
| Open AccessSingle cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease
What happens to cells on engrafting into the brain in animal models to treat Parkinson’s disease is unclear. Here, the authors use scRNA-seq to examine ventral midbrain (VM)-patterned human embryonic stem cells after functional maturation in a pre-clinical rat model for Parkinson’s disease and identify perivascular-like cells.
- Katarína Tiklová
- , Sara Nolbrant
- & Malin Parmar
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Article
| Open AccessThe in vivo genetic program of murine primordial lung epithelial progenitors
The identity of the earliest murine in vivo lung epithelial progenitors (marked by NKX2-1 expression) is unclear. Here, the authors use single-cell RNA sequencing to define the genetic program of these lung primordial progenitors, which will improve in vitro lung specification of pluripotent stem cells.
- Laertis Ikonomou
- , Michael J. Herriges
- & Darrell N. Kotton
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Article
| Open AccessErythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration
Gut microbiota and their metabolites regulate homeostasis of the intestine, but their effects on intestine development are unclear. Here the authors use RNAseq and germ free mice to show that intestinal microbiota promote the expression of Erdr1, which increases Lgr5+ intestinal stem cell number and activity.
- Hirohito Abo
- , Benoit Chassaing
- & Timothy L. Denning
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Article
| Open AccessSertoli cell ablation and replacement of the spermatogonial niche in mouse
Sertoli cells and other somatic cells of the testis comprise the germ cell niche and are critical to regulate spermatogenesis. Here the authors present a method in which Sertoli cells are selectively targeted for ablation by the compound benzalkonium chloride (BC) in mice, and the spermatogenic niche is subsequently repopulated in regions that have been affected by BC treatment.
- Tetsuhiro Yokonishi
- , Jennifer McKey
- & Blanche Capel
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Article
| Open AccessIRF2 is a master regulator of human keratinocyte stem cell fate
Epidermal homeostasis requires long term stem cell function. Here, the authors apply transcriptional circuitry analysis based on integrated epigenomic profiling of primary human keratinocytes with high and low stem cell function to identify IRF2 as a negative regulator of stemness.
- Nicolas Mercado
- , Gabi Schutzius
- & Susan Kirkland
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Article
| Open AccessConnective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence
In regenerative animals, how cells respond to injury signals inducing senescence is unclear. Here, the authors show that cells from highly regenerative mammals are resistant to ROS-induced cellular senescence, but non-regenerating species exhibit mitochondrial dysfunction/senescence in response to hydrogen peroxide exposure.
- Sandeep Saxena
- , Hemendra Vekaria
- & Ashley W. Seifert
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Article
| Open AccessDamage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut
Epithelia are exposed to diverse types of environmental stress, but the mechanisms by which epithelial cells sense stress are not well understood. Here, the authors show that a Nox-ROS-Ask1-MKK3-p38 signaling axis integrates various types of stress to promote intestinal regeneration.
- Parthive H. Patel
- , Clothilde Pénalva
- & Bruce A. Edgar
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Article
| Open AccessSOX11 and SOX4 drive the reactivation of an embryonic gene program during murine wound repair
Wounding induces changes in cell identity but the mechanisms regulating this are unclear. Here, the authors show that Sox11/Sox4 expression in the leading edge of wounds converts murine epidermal cells to an embryonic-like state and facilitates repair.
- Qi Miao
- , Matthew C. Hill
- & Hoang Nguyen
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Article
| Open AccessPriming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy
Hair follicles (HFs) are sensitive to chemotherapy but recover from quiescent HF stem cells, although sometimes chemotherapy results in permanent loss. Here, Kim et al. establish a model of permanent chemotherapy-induced alopecia to uncover the underlying mechanisms depleting human HF stem cells.
- Jin Yong Kim
- , Jungyoon Ohn
- & Ohsang Kwon
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Article
| Open AccessStabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis
DGCR8 is a component of the canonical microprocessor complex for microRNA biogenesis. Here the authors implicate DGCR8 in heterochromatin maintenance and aging attenuation independent of its miRNA-processing activity through Lamin B1, KAP1 and HP1 interaction. DGCR8 overexpression can alleviate aging and senescence
- Liping Deng
- , Ruotong Ren
- & Guang-Hui Liu
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Article
| Open AccessDual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction
Myocardial infarction causes damage to the myocardium and vasculature. Here the authors show in a rat model of myocardial infarction that cardiomyocytes derived from human induced pluripotent stem cells combined with a human mesenchymal stem cell-loaded patch lead to improved cardiac function and promote vessel formation.
- Soon-Jung Park
- , Ri Youn Kim
- & Hun-Jun Park
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Article
| Open AccessAWD regulates timed activation of BMP signaling in intestinal stem cells to maintain tissue homeostasis
Regeneration after injury in the Drosophila intestine involves early activation of intestinal stem cells (ISCs) and subsequent return to quiescence. Here the authors show that return to quiescence by ISCs involves BMP Type I receptor Tkv protein stabilization along with AWD mediated internalization into endocytic vesicles.
- Xiaoyu Tracy Cai
- , Hongjie Li
- & Heinrich Jasper
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Article
| Open AccessBioinspired extracellular vesicles embedded with black phosphorus for molecular recognition-guided biomineralization
Bone regeneration is of interest for treating a wide range of medical conditions. Here, the authors report on bioinspired matrix vesicles loaded with black phosphorus nanosheets and cell-specific aptamers for bone regeneration and demonstrate bone defect repair in vivo.
- Yingqian Wang
- , Xiaoxia Hu
- & Quan Yuan
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Article
| Open AccessSox17 is required for endothelial regeneration following inflammation-induced vascular injury
Endothelial cell regeneration is essential for blood vessels to recover from inflammation-induced injury. Here Liu et al. show that the transcription factor Sox17 is required for endothelial regeneration following endotoxemia, and that delivery of a transgene expressing Sox17 to lung endothelial cells enhances recovery after injury.
- Menglin Liu
- , Lianghui Zhang
- & Asrar B. Malik
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Article
| Open AccessRegeneration of severely damaged lungs using an interventional cross-circulation platform
Gastric aspiration severely injures donor lungs, frequently making them unacceptable for transplantation. Here the authors show that an interventional cross-circulation platform enables the regeneration of severely damaged lungs in a swine model of gastric aspiration injury.
- Brandon A. Guenthart
- , John D. O’Neill
- & Matthew Bacchetta
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Article
| Open AccessMuscle functions as a connective tissue and source of extracellular matrix in planarians
How the cellular source of positional information compares across regenerative animals is unclear. Here, the authors find that planarian muscle, which harbours positional information, acts as a connective tissue by being a major site of matrisome gene expression and by maintaining tissue architecture.
- Lauren E. Cote
- , Eric Simental
- & Peter W. Reddien
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Article
| Open AccessRole of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming
Fibroblasts can be directly reprogrammed to cardiomyocytes, but reprogramming is less efficient for adult compared to embryonic fibroblasts. Here, the authors find that inhibition of inflammation and Cox-2-prostaglandin-cAMP-IL-1β signaling enhances reprogramming efficiency of adult, but not embryonic fibroblasts.
- Naoto Muraoka
- , Kaori Nara
- & Masaki Ieda
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Article
| Open AccessSingle-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds
The diversity of fibroblasts contributing to wound healing is unclear. Here, the authors use single-cell RNA-sequencing to identify heterogeneity among murine fibroblasts in the wound and find that recruited myeloid cells contribute to adipocyte regeneration during healing.
- Christian F. Guerrero-Juarez
- , Priya H. Dedhia
- & Maksim V. Plikus
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Article
| Open AccessBMP9 stimulates joint regeneration at digit amputation wounds in mice
Mammalian joints have poor regenerative capacity following amputation. Here, the authors show that in mice, stimulation of the amputation wound with BMP2 and BMP9 stimulates regeneration of a synovial joint that includes bone, cartilage and a synovial cavity.
- Ling Yu
- , Lindsay A. Dawson
- & Ken Muneoka
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Article
| Open AccessTranscriptomic landscape of the blastema niche in regenerating adult axolotl limbs at single-cell resolution
Limb regeneration requires a blastema with progenitor cells, immune cells, and an overlying wound epidermis, but molecular identities of these populations are unclear. Here, the authors use single-cell RNA-sequencing to identify transcriptionally distinct cell populations in adult axolotl limb blastemas.
- Nicholas D. Leigh
- , Garrett S. Dunlap
- & Jessica L. Whited
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Article
| Open AccessA biomaterial with a channel-like pore architecture induces endochondral healing of bone defects
A bioengineering approach to enhance the regeneration of large bone defects is lacking. Here, the authors show that a biomaterial scaffold with a channel-like pore architecture enables organized endochondral ossification through directional cell recruitment and extracellular matrix alignment.
- A. Petersen
- , A. Princ
- & G. N. Duda
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Article
| Open AccessEpigenomic map of human liver reveals principles of zonated morphogenic and metabolic control
Spatial mapping of genomic programs in tissue cells is an important step in the understanding of organ function and disease. Here, the authors provide a spatially resolved epigenomic and transcriptomic map of human liver and show porto-central gradients in metabolic and morphogen networks and transcription factor binding sites as a basis to better understand liver regeneration and function.
- Mario Brosch
- , Kathrin Kattler
- & Jochen Hampe
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Article
| Open AccessDamage-induced reactive oxygen species enable zebrafish tail regeneration by repositioning of Hedgehog expressing cells
Reactive oxygen species (ROS) are required to initiate regeneration but the mechanisms regulating its production are unclear. Here, the authors show in zebrafish larval tail regeneration that ROS is released by mobilised notochord cells enables their repositioning in the damage site, assisted by secreted Hh.
- Maria Montserrat Garcia Romero
- , Gareth McCathie
- & Henry Hamilton Roehl
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Article
| Open AccessIdentification of dynamic undifferentiated cell states within the male germline
Sustained spermatogenesis depends on stem cell activity which is contained within a population of undifferentiated spermatogonia. Here, the authors identify a new population of undifferentiated spermatogonia in adult testis that expresses the transcription factor PDX1 and has stem cell capacity.
- Hue M. La
- , Juho-Antti Mäkelä
- & Robin M. Hobbs
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Article
| Open AccessEndocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury
The recovery of function upon acute kidney injury is thought to involve tubular cell dedifferentiation and proliferation. Here the authors show that Pax2+ progenitors regenerate tubules via cell division while other tubular cells support function recovery by undergoing hypertrophy through endoreplication.
- Elena Lazzeri
- , Maria Lucia Angelotti
- & Paola Romagnani
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Article
| Open AccessHCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns
The authors have previously shown that membrane voltage can influence embryonic patterning during development. Here, the authors computationally model how nicotine disrupts Xenopus embryogenesis by perturbing voltage gradients, and rescue nicotine-inducted defects with HCN2 channel expression.
- Vaibhav P. Pai
- , Alexis Pietak
- & Michael Levin
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Article
| Open AccessPeriosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin
The periosteum, a tissue lining the bone surface, and the bone marrow are known to contain bone-forming cells. Here the authors show that skeletal stem cells reside in the mouse periosteum, and that periosteal cells have common embryonic origins with bone marrow stromal/stem cells (BMSCs), but are better at bone repair and long-term integration than BMSCs.
- Oriane Duchamp de Lageneste
- , Anaïs Julien
- & Céline Colnot
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Article
| Open AccessTbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration
It is not clear if it is the embryonic origin or anatomical location of cardiomyocytes that restrict their contribution to zebrafish heart regeneration. Here, the authors show a plasticity of embryonic precursors following tbx5a fate mapping and that trabecular cardiomyocytes help to rebuild the cortical myocardium.
- Héctor Sánchez-Iranzo
- , María Galardi-Castilla
- & Nadia Mercader
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Article
| Open AccessReading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration
The Iberian ribbed newt Pleurodeles waltl has a wide spectrum of regeneration abilities. Here, Elewa et al. sequence its ~20 Gb genome and transcriptome to investigate the molecular features underlying its regenerative capacities.
- Ahmed Elewa
- , Heng Wang
- & András Simon