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1.
Annu Rev Immunol ; 41: 207-228, 2023 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-36696569

RESUMEN

The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Piel , Humanos , Animales , Epitelio , Regeneración/fisiología
2.
Nat Rev Mol Cell Biol ; 25(8): 654-670, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38600372

RESUMEN

From embryonic development, postnatal growth and adult homeostasis to reparative and disease states, cells and tissues undergo constant changes in genome activity, cell fate, proliferation, movement, metabolism and growth. Importantly, these biological state transitions are coupled to changes in the mechanical and material properties of cells and tissues, termed mechanical state transitions. These mechanical states share features with physical states of matter, liquids and solids. Tissues can switch between mechanical states by changing behavioural dynamics or connectivity between cells. Conversely, these changes in tissue mechanical properties are known to control cell and tissue function, most importantly the ability of cells to move or tissues to deform. Thus, tissue mechanical state transitions are implicated in transmitting information across biological length and time scales, especially during processes of early development, wound healing and diseases such as cancer. This Review will focus on the biological basis of tissue-scale mechanical state transitions, how they emerge from molecular and cellular interactions, and their roles in organismal development, homeostasis, regeneration and disease.


Asunto(s)
Homeostasis , Humanos , Animales , Homeostasis/fisiología , Fenómenos Biomecánicos , Desarrollo Embrionario/fisiología , Regeneración/fisiología , Cicatrización de Heridas/fisiología
3.
Nat Rev Mol Cell Biol ; 25(9): 720-739, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38684869

RESUMEN

Epithelial-mesenchymal transitions (EMTs) are the epitome of cell plasticity in embryonic development and cancer; during EMT, epithelial cells undergo dramatic phenotypic changes and become able to migrate to form different tissues or give rise to metastases, respectively. The importance of EMTs in other contexts, such as tissue repair and fibrosis in the adult, has become increasingly recognized and studied. In this Review, we discuss the function of EMT in the adult after tissue damage and compare features of embryonic and adult EMT. Whereas sustained EMT leads to adult tissue degeneration, fibrosis and organ failure, its transient activation, which confers phenotypic and functional plasticity on somatic cells, promotes tissue repair after damage. Understanding the mechanisms and temporal regulation of different EMTs provides insight into how some tissues heal and has the potential to open new therapeutic avenues to promote repair or regeneration of tissue damage that is currently irreversible. We also discuss therapeutic strategies that modulate EMT that hold clinical promise in ameliorating fibrosis, and how precise EMT activation could be harnessed to enhance tissue repair.


Asunto(s)
Transición Epitelial-Mesenquimal , Fibrosis , Humanos , Animales , Cicatrización de Heridas/fisiología , Regeneración/fisiología , Células Epiteliales/patología , Células Epiteliales/metabolismo
4.
Cell ; 184(1): 243-256.e18, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33417861

RESUMEN

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.


Asunto(s)
Cognición/fisiología , Suturas Craneales/fisiopatología , Craneosinostosis/fisiopatología , Regeneración/fisiología , Cráneo/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Craneosinostosis/genética , Duramadre/patología , Duramadre/fisiopatología , Gelatina/farmacología , Perfilación de la Expresión Génica , Fuerza de la Mano , Presión Intracraneal/efectos de los fármacos , Presión Intracraneal/fisiología , Locomoción/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Metacrilatos/farmacología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Regeneración/efectos de los fármacos , Cráneo/patología , Proteína 1 Relacionada con Twist/metabolismo , Vía de Señalización Wnt/efectos de los fármacos
5.
Cell ; 176(5): 1128-1142.e18, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30686582

RESUMEN

Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.


Asunto(s)
Circulación Colateral/fisiología , Corazón/crecimiento & desarrollo , Regeneración/fisiología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Quimiocina CXCL12/metabolismo , Vasos Coronarios/crecimiento & desarrollo , Células Endoteliales/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Receptores CXCR4/metabolismo , Transducción de Señal
6.
Cell ; 177(4): 957-969.e13, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31051107

RESUMEN

Patterning in plants relies on oriented cell divisions and acquisition of specific cell identities. Plants regularly endure wounds caused by abiotic or biotic environmental stimuli and have developed extraordinary abilities to restore their tissues after injuries. Here, we provide insight into a mechanism of restorative patterning that repairs tissues after wounding. Laser-assisted elimination of different cells in Arabidopsis root combined with live-imaging tracking during vertical growth allowed analysis of the regeneration processes in vivo. Specifically, the cells adjacent to the inner side of the injury re-activated their stem cell transcriptional programs. They accelerated their progression through cell cycle, coordinately changed the cell division orientation, and ultimately acquired de novo the correct cell fates to replace missing cells. These observations highlight existence of unknown intercellular positional signaling and demonstrate the capability of specified cells to re-acquire stem cell programs as a crucial part of the plant-specific mechanism of wound healing.


Asunto(s)
Raíces de Plantas/metabolismo , Células Madre/metabolismo , Cicatrización de Heridas/fisiología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Diferenciación Celular/fisiología , División Celular , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/metabolismo , Regeneración/fisiología , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo
7.
Cell ; 177(4): 942-956.e14, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30955889

RESUMEN

Plants are sessile and have to cope with environmentally induced damage through modification of growth and defense pathways. How tissue regeneration is triggered in such responses and whether this involves stem cell activation is an open question. The stress hormone jasmonate (JA) plays well-established roles in wounding and defense responses. JA also affects growth, which is hitherto interpreted as a trade-off between growth and defense. Here, we describe a molecular network triggered by wound-induced JA that promotes stem cell activation and regeneration. JA regulates organizer cell activity in the root stem cell niche through the RBR-SCR network and stress response protein ERF115. Moreover, JA-induced ERF109 transcription stimulates CYCD6;1 expression, functions upstream of ERF115, and promotes regeneration. Soil penetration and response to nematode herbivory induce and require this JA-mediated regeneration response. Therefore, the JA tissue damage response pathway induces stem cell activation and regeneration and activates growth after environmental stress.


Asunto(s)
Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Raíces de Plantas/metabolismo , Células Madre/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Ciclinas/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Herbivoria , Ácidos Indolacéticos/metabolismo , Regeneración/fisiología , Transducción de Señal/fisiología , Estrés Fisiológico , Factores de Transcripción/metabolismo
8.
Cell ; 177(3): 608-621.e12, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30955891

RESUMEN

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.


Asunto(s)
Hepatopatías/patología , Hígado/metabolismo , Regeneración , Animales , Enfermedad Crónica , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Hidrolasas/deficiencia , Hidrolasas/genética , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Hepatopatías/genética , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regeneración/fisiología , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuenciación del Exoma
9.
Cell ; 175(2): 327-345, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30290140

RESUMEN

Regeneration is one of the great mysteries of biology. Planarians are flatworms capable of dramatic feats of regeneration, which have been studied for over 2 centuries. Recent findings identify key cellular and molecular principles underlying these feats. A stem cell population (neoblasts) generates new cells and is comprised of pluripotent stem cells (cNeoblasts) and fate-specified cells (specialized neoblasts). Positional information is constitutively active and harbored primarily in muscle, where it acts to guide stem cell-mediated tissue turnover and regeneration. I describe here a model in which positional information and stem cells combine to enable regeneration.


Asunto(s)
Planarias/fisiología , Regeneración/fisiología , Animales , Diferenciación Celular/fisiología , Planarias/genética , Células Madre Pluripotentes/fisiología , Células Madre/fisiología
10.
Annu Rev Cell Dev Biol ; 35: 501-521, 2019 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-31590586

RESUMEN

The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting upstream of stress-responsive JNK and p38 MAP kinases, DLK and LZK have emerged as central players in neuronal responses to a variety of acute and traumatic injuries. Recent studies also implicate their function in astrocytes, microglia, and other nonneuronal cells, reflecting their expanding roles in the multicellular response to injury and in disease. Of particular note is the potential link of these kinases to neurodegenerative diseases and cancer. It is thus critical to understand the physiological contexts under which these kinases are activated, as well as the signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide a historical overview of the biochemical and functional dissection of these kinases. We then discuss recent findings on regulating their activity to enhance cellular protection following injury and in disease, focusing on but not limited to the nervous system.


Asunto(s)
Leucina Zippers/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Neuronas/metabolismo , Estrés Fisiológico/genética , Animales , Axones/metabolismo , Humanos , Quinasas Quinasa Quinasa PAM/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/virología , Neuroglía/metabolismo , Neuronas/virología , Regeneración/genética , Regeneración/fisiología , Células Madre/metabolismo , Estrés Fisiológico/fisiología , Heridas y Lesiones/genética , Heridas y Lesiones/metabolismo
11.
Annu Rev Cell Dev Biol ; 35: 567-589, 2019 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-31553635

RESUMEN

Deafness or hearing deficits are debilitating conditions. They are often caused by loss of sensory hair cells or defects in their function. In contrast to mammals, nonmammalian vertebrates robustly regenerate hair cells after injury. Studying the molecular and cellular basis of nonmammalian vertebrate hair cell regeneration provides valuable insights into developing cures for human deafness. In this review, we discuss the current literature on hair cell regeneration in the context of other models for sensory cell regeneration, such as the retina and the olfactory epithelium. This comparison reveals commonalities with, as well as differences between, the different regenerating systems, which begin to define a cellular and molecular blueprint of regeneration. In addition, we propose how new technical advances can address outstanding questions in the field.


Asunto(s)
Células Madre Adultas/metabolismo , Oído Interno/metabolismo , Células Ciliadas Auditivas/fisiología , Mucosa Olfatoria/metabolismo , Regeneración/fisiología , Retina/metabolismo , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Citocinas/metabolismo , Oído Interno/citología , Células Ciliadas Auditivas/citología , Células Ciliadas Auditivas/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Macrófagos/metabolismo , Regeneración/genética , Retina/citología , Transducción de Señal/genética , Transducción de Señal/fisiología , Heridas y Lesiones/genética , Heridas y Lesiones/metabolismo
12.
Nat Rev Mol Cell Biol ; 21(11): 696-711, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32901139

RESUMEN

Bone development occurs through a series of synchronous events that result in the formation of the body scaffold. The repair potential of bone and its surrounding microenvironment - including inflammatory, endothelial and Schwann cells - persists throughout adulthood, enabling restoration of tissue to its homeostatic functional state. The isolation of a single skeletal stem cell population through cell surface markers and the development of single-cell technologies are enabling precise elucidation of cellular activity and fate during bone repair by providing key insights into the mechanisms that maintain and regenerate bone during homeostasis and repair. Increased understanding of bone development, as well as normal and aberrant bone repair, has important therapeutic implications for the treatment of bone disease and ageing-related degeneration.


Asunto(s)
Desarrollo Óseo/fisiología , Enfermedades Óseas/fisiopatología , Huesos/fisiología , Regeneración/fisiología , Animales , Humanos
14.
Nat Rev Mol Cell Biol ; 20(12): 753-765, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31690888

RESUMEN

Tracking the progeny of single cells is necessary for building lineage trees that recapitulate processes such as embryonic development and stem cell differentiation. In classical lineage tracing experiments, cells are fluorescently labelled to allow identification by microscopy of a limited number of cell clones. To track a larger number of clones in complex tissues, fluorescent proteins are now replaced by heritable DNA barcodes that are read using next-generation sequencing. In prospective lineage tracing, unique DNA barcodes are introduced into single cells through genetic manipulation (using, for example, Cre-mediated recombination or CRISPR-Cas9-mediated editing) and tracked over time. Alternatively, in retrospective lineage tracing, naturally occurring somatic mutations can be used as endogenous DNA barcodes. Finally, single-cell mRNA-sequencing datasets that capture different cell states within a developmental or differentiation trajectory can be used to recapitulate lineages. In this Review, we discuss methods for prospective or retrospective lineage tracing and demonstrate how trajectory reconstruction algorithms can be applied to single-cell mRNA-sequencing datasets to infer developmental or differentiation tracks. We discuss how these approaches are used to understand cell fate during embryogenesis, cell differentiation and tissue regeneration.


Asunto(s)
Sistemas CRISPR-Cas , Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Desarrollo Embrionario/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Regeneración/fisiología , Animales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos
15.
Nature ; 633(8031): 895-904, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39169180

RESUMEN

For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans1-6. However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5+ ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast-refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.


Asunto(s)
Carcinogénesis , Colon , Ayuno , Conducta Alimentaria , Intestino Delgado , Poliaminas , Células Madre , Animales , Femenino , Masculino , Ratones , Carcinogénesis/metabolismo , Carcinogénesis/patología , Proliferación Celular , Colon/citología , Colon/metabolismo , Colon/patología , Dieta , Ayuno/fisiología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Intestino Delgado/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neoplasias/patología , Poliaminas/metabolismo , Biosíntesis de Proteínas , Receptores Acoplados a Proteínas G/metabolismo , Regeneración/fisiología , Medición de Riesgo , Células Madre/citología , Células Madre/metabolismo , Células Madre/patología , Factores de Tiempo , Conducta Alimentaria/fisiología , Proteína de la Poliposis Adenomatosa del Colon/deficiencia , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo
16.
Annu Rev Cell Dev Biol ; 32: 609-631, 2016 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-27146311

RESUMEN

Classically, white adipose tissue (WAT) was considered an inert component of connective tissue but is now appreciated as a major regulator of metabolic physiology and endocrine homeostasis. Recent work defining how WAT develops and expands in vivo emphasizes the importance of specific locations of WAT or depots in metabolic regulation. Interestingly, mature white adipocytes are integrated into several tissues. A new perspective regarding the in vivo regulation and function of WAT in these tissues has highlighted an essential role of adipocytes in tissue homeostasis and regeneration. Finally, there has been significant progress in understanding how mature adipocytes regulate the pathology of several diseases. In this review, we discuss these novel roles of WAT in the homeostasis and regeneration of epithelial, muscle, and immune tissues and how they contribute to the pathology of several disorders.


Asunto(s)
Adipocitos/metabolismo , Organogénesis , Regeneración/fisiología , Nicho de Células Madre , Animales , Enfermedad , Humanos , Modelos Biológicos
17.
Physiol Rev ; 102(3): 1495-1552, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35343828

RESUMEN

Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.


Asunto(s)
Regeneración , Glándulas Salivales , Linaje de la Célula , Humanos , Salud Bucal , Regeneración/fisiología , Glándulas Salivales/fisiología , Transducción de Señal
18.
Nat Rev Mol Cell Biol ; 18(12): 728-742, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29115301

RESUMEN

Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.


Asunto(s)
Células Madre Adultas/fisiología , Matriz Extracelular/fisiología , Organogénesis/fisiología , Regeneración/fisiología , Nicho de Células Madre/fisiología , Células Madre Adultas/citología , Animales , Fenómenos Biomecánicos/fisiología , Humanos
19.
Nature ; 622(7983): 619-626, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37758950

RESUMEN

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.


Asunto(s)
Reprogramación Celular , Ácidos Grasos , Corazón , Regeneración , Animales , Ratones , Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/genética , Hipoxia de la Célula , Proliferación Celular , Metabolismo Energético , Activación Enzimática , Epigénesis Genética , Ácidos Grasos/metabolismo , Corazón/fisiología , Histona Demetilasas/metabolismo , Ácidos Cetoglutáricos/metabolismo , Mutación , Miocardio , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Oxidación-Reducción , Regeneración/fisiología , Daño por Reperfusión , Transcripción Genética
20.
Nature ; 620(7972): 163-171, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37495694

RESUMEN

An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot1. Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl (Ambystoma mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.


Asunto(s)
Ambystoma mexicanum , Evolución Biológica , Biosíntesis de Proteínas , Regeneración , Serina-Treonina Quinasas TOR , Animales , Humanos , Ratones , Ambystoma mexicanum/fisiología , Secuencia de Aminoácidos , Extremidades/fisiología , Regeneración/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Cicatrización de Heridas , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Especificidad de la Especie , Antioxidantes/metabolismo , Nutrientes/metabolismo , Polirribosomas/genética , Polirribosomas/metabolismo
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