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1.
Elife ; 122023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36719070

RESUMEN

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.


Asunto(s)
Ayuno Intermitente , Regeneración Hepática , Ratones , Animales , Hígado , Ayuno , Hepatocitos , Proliferación Celular
2.
Cell Rep ; 23(2): 361-375, 2018 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-29641997

RESUMEN

Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.


Asunto(s)
Reprogramación Celular , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína de Retinoblastoma/metabolismo , Antígenos de Superficie/metabolismo , Línea Celular , Proliferación Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Fosforilación , Proteoglicanos/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteína de Retinoblastoma/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
3.
Circ Res ; 121(6): e22-e36, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28743804

RESUMEN

RATIONALE: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. OBJECTIVE: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model. METHODS AND RESULTS: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. CONCLUSIONS: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.


Asunto(s)
Células Madre Pluripotentes Inducidas/trasplante , Infarto del Miocardio/terapia , Miocitos Cardíacos/trasplante , Animales , Línea Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/trasplante , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Comunicación Paracrina , Trasplante de Células Madre/métodos
4.
Circ Res ; 116(7): e40-50, 2015 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-25654979

RESUMEN

RATIONALE: The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit(+)AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs). OBJECTIVE: To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging. METHODS AND RESULTS: SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit(+)AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit(+)AMC-treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation. CONCLUSION: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.


Asunto(s)
Células Madre Pluripotentes Inducidas/trasplante , Imagen por Resonancia Magnética/métodos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Imagen Multimodal , Infarto del Miocardio/terapia , Miocardio/patología , Animales , Separación Celular/métodos , Supervivencia Celular , Estenosis Coronaria/complicaciones , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Genes Reporteros , Supervivencia de Injerto , Xenoinjertos , Humanos , Ligadura , Mediciones Luminiscentes , Masculino , Manganeso , Células Madre Mesenquimatosas/química , Ratones , Ratones Mutantes , Ratones SCID , Infarto del Miocardio/etiología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Placenta/citología , Embarazo , Proteínas Proto-Oncogénicas c-kit/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homeostasis del Telómero , Función Ventricular Izquierda
5.
Development ; 138(24): 5379-91, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22071105

RESUMEN

Interactions of hematopoietic cells with their microenvironment control blood cell colonization, homing and hematopoiesis. Here, we introduce larval hematopoiesis as the first Drosophila model for hematopoietic colonization and the role of the peripheral nervous system (PNS) as a microenvironment in hematopoiesis. The Drosophila larval hematopoietic system is founded by differentiated hemocytes of the embryo, which colonize segmentally repeated epidermal-muscular pockets and proliferate in these locations. Importantly, we show that these resident hemocytes tightly colocalize with peripheral neurons and we demonstrate that larval hemocytes depend on the PNS as an attractive and trophic microenvironment. atonal (ato) mutant or genetically ablated larvae, which are deficient for subsets of peripheral neurons, show a progressive apoptotic decline in hemocytes and an incomplete resident hemocyte pattern, whereas supernumerary peripheral neurons induced by ectopic expression of the proneural gene scute (sc) misdirect hemocytes to these ectopic locations. This PNS-hematopoietic connection in Drosophila parallels the emerging role of the PNS in hematopoiesis and immune functions in vertebrates, and provides the basis for the systematic genetic dissection of the PNS-hematopoietic axis in the future.


Asunto(s)
Células Sanguíneas/fisiología , Movimiento Celular/fisiología , Drosophila melanogaster/fisiología , Sistema Nervioso Periférico/fisiología , Animales , Apoptosis/fisiología , Proliferación Celular , Supervivencia Celular/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiología , Drosophila melanogaster/genética , Hematopoyesis/fisiología , Larva/genética , Larva/fisiología , Neuronas/fisiología , Factores de Transcripción/genética , Factores de Transcripción/fisiología
6.
Development ; 138(14): 2883-93, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21653613

RESUMEN

We used the brain insulin-producing cell (IPC) lineage and its identified neuroblast (IPC NB) as a model to understand a novel example of serial specification of NB identities in the Drosophila dorsomedial protocerebral neuroectoderm. The IPC NB was specified from a small, molecularly identified group of cells comprising an invaginated epithelial placode. By progressive delamination of cells, the placode generated a series of NB identities, including the single IPC NB, a number of other canonical Type I NBs, and a single Type II NB that generates large lineages by transient amplification of neural progenitor cells. Loss of Notch function caused all cells of the placode to form as supernumerary IPC NBs, indicating that the placode is initially a fate equivalence group for the IPC NB fate. Loss of Egfr function caused all placodal cells to apoptose, except for the IPC NB, indicating a requirement of Egfr signaling for specification of alternative NB identities. Indeed, both derepressed Egfr activity in yan mutants and ectopic EGF activity produced supernumerary Type II NBs from the placode. Loss of both Notch and Egfr function caused all placode cells to become IPC NBs and survive, indicating that commitment to NB fate nullified the requirement of Egfr activity for placode cell survival. We discuss the surprising parallels between the serial specification of neural fates from this neurogenic placode and the fly retina.


Asunto(s)
Encéfalo/citología , Diferenciación Celular/fisiología , Proteínas de Drosophila/metabolismo , Drosophila/embriología , Receptores ErbB/metabolismo , Placa Neural/embriología , Neuronas/fisiología , Receptores de Péptidos de Invertebrados/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Animales , Encéfalo/embriología , Bromodesoxiuridina , Linaje de la Célula/fisiología , Cartilla de ADN/genética , Inmunohistoquímica , Placa Neural/metabolismo , Neuronas/metabolismo , Temperatura
7.
Cell Metab ; 10(3): 199-207, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19723496

RESUMEN

Insulin-like peptides (ILPs) couple growth, metabolism, longevity, and fertility with changes in nutritional availability. In Drosophila, several ILPs called Dilps are produced by the brain insulin-producing cells (IPCs), from which they are released into the hemolymph and act systemically. We show here that in response to nutrient deprivation, brain Dilps are no longer secreted and accumulate in the IPCs. We further demonstrate that the larval fat body, a functional homolog of vertebrate liver and white fat, couples the level of circulating Dilps with dietary amino acid levels by remotely controlling Dilp release through a TOR/RAPTOR-dependent mechanism. We finally use ex vivo tissue coculture to demonstrate that a humoral signal emitted by the fat body transits through the hemolymph and activates Dilp secretion in the IPCs. Thus, the availability of nutrients is remotely sensed in fat body cells and conveyed to the brain IPCs by a humoral signal controlling ILP release.


Asunto(s)
Adipocitos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Insulina/metabolismo , Neuropéptidos/metabolismo , Animales , Encéfalo/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Larva/metabolismo
8.
Cell Metab ; 7(4): 281-3, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18396131

RESUMEN

In Drosophila, a simple network of nutrient-sensing neuroendocrine cells, analogs of pancreatic islet alpha and beta cells, regulates carbohydrate metabolism. Work presented in this issue of Cell Metabolism (Buch et al., 2008) shows that signals from these cells control expression of a glycogen-specific glucosidase in response to dietary protein and carbohydrate.


Asunto(s)
Dieta , Carbohidratos de la Dieta/farmacología , Proteínas en la Dieta/farmacología , Drosophila melanogaster/efectos de los fármacos , Sistemas Neurosecretores/efectos de los fármacos , alfa-Glucosidasas/metabolismo , Animales , Metabolismo de los Hidratos de Carbono , Carbohidratos de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Drosophila melanogaster/enzimología , Drosophila melanogaster/metabolismo , Glucógeno/metabolismo , Humanos , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/metabolismo
9.
Proc Natl Acad Sci U S A ; 104(50): 19873-8, 2007 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-18056636

RESUMEN

Single-cell resolution lineage information is a critical key to understanding how the states of gene regulatory networks respond to cell interactions and thereby establish distinct cell fates. Here, we identify a single pair of neural stem cells (neuroblasts) as progenitors of the brain insulin-producing neurosecretory cells of Drosophila, which are homologous to islet beta cells. Likewise, we identify a second pair of neuroblasts as progenitors of the neurosecretory Corpora cardiaca cells, which are homologous to the glucagon-secreting islet alpha cells. We find that both progenitors originate as neighboring cells from anterior neuroectoderm, which expresses genes orthologous to those expressed in the vertebrate adenohypophyseal placode, the source of endocrine anterior pituitary and neurosecretory hypothalamic cells [Whitlock KE (2005) Trends Endocrinol Metab 16:145-151]. This ontogenic-molecular concordance suggests that a rudimentary brain endocrine axis was present in the common ancestor of humans and flies, where it orchestrated the islet-like endocrine functions of insulin and glucagon biology.


Asunto(s)
Diferenciación Celular , Drosophila melanogaster/citología , Sistema Endocrino , Islotes Pancreáticos/citología , Animales , Animales Modificados Genéticamente , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Linaje de la Célula , Drosophila melanogaster/embriología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Regulación del Desarrollo de la Expresión Génica , Insulina/metabolismo , Islotes Pancreáticos/metabolismo
10.
Nature ; 431(7006): 316-20, 2004 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-15372035

RESUMEN

Antagonistic activities of glucagon and insulin control metabolism in mammals, and disruption of this balance underlies diabetes pathogenesis. Insulin-producing cells (IPCs) in the brain of insects such as Drosophila also regulate serum glucose, but it remains unclear whether insulin is the sole hormonal regulator of glucose homeostasis and whether mechanisms of glucose-sensing and response in IPCs resemble those in pancreatic islets. Here we show, by targeted cell ablation, that Drosophila corpora cardiaca (CC) cells of the ring gland are also essential for larval glucose homeostasis. Unlike IPCs, CC cells express Drosophila cognates of sulphonylurea receptor (Sur) and potassium channel (Ir), proteins that comprise ATP-sensitive potassium channels regulating hormone secretion by islets and other mammalian glucose-sensing cells. They also produce adipokinetic hormone, a polypeptide with glucagon-like functions. Glucose regulation by CC cells is impaired by exposure to sulphonylureas, drugs that target the Sur subunit. Furthermore, ubiquitous expression of an akh transgene reverses the effect of CC ablation on serum glucose. Thus, Drosophila CC cells are crucial regulators of glucose homeostasis and they use glucose-sensing and response mechanisms similar to islet cells.


Asunto(s)
Drosophila/citología , Drosophila/metabolismo , Glándulas Endocrinas/citología , Glándulas Endocrinas/fisiología , Glucosa/metabolismo , Homeostasis , Canales de Potasio de Rectificación Interna , Transportadoras de Casetes de Unión a ATP/agonistas , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Genes de Insecto/genética , Hemolinfa/metabolismo , Hormonas de Insectos/genética , Hormonas de Insectos/metabolismo , Larva/metabolismo , Oligopéptidos/genética , Oligopéptidos/metabolismo , Canales de Potasio/agonistas , Canales de Potasio/metabolismo , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptores de Droga/agonistas , Receptores de Droga/metabolismo , Compuestos de Sulfonilurea/farmacología , Receptores de Sulfonilureas , Transgenes/genética
11.
Science ; 296(5570): 1118-20, 2002 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-12004130

RESUMEN

In the fruit fly Drosophila, four insulin genes are coexpressed in small clusters of cells [insulin-producing cells (IPCs)] in the brain. Here, we show that ablation of these IPCs causes developmental delay, growth retardation, and elevated carbohydrate levels in larval hemolymph. All of the defects were reversed by ectopic expression of a Drosophila insulin transgene. On the basis of these functional data and the observation that IPCs release insulin into the circulatory system, we conclude that brain IPCs are the main systemic supply of insulin during larval growth. We propose that IPCs and pancreatic islet beta cells are functionally analogous and may have evolved from a common ancestral insulin-producing neuron. Interestingly, the phenotype of flies lacking IPCs includes certain features of diabetes mellitus.


Asunto(s)
Glucemia/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/fisiología , Insulina/metabolismo , Neuronas/metabolismo , Trehalosa/sangre , Animales , Animales Modificados Genéticamente , Encéfalo/citología , Recuento de Células , Tamaño de la Célula , Diabetes Mellitus , Drosophila/anatomía & histología , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Expresión Génica , Corazón/inervación , Hemolinfa , Hormonas de Insectos/genética , Hormonas de Insectos/metabolismo , Insulina/genética , Larva/crecimiento & desarrollo , Miocardio/metabolismo , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/metabolismo , Oligopéptidos/genética , Oligopéptidos/metabolismo , Fenotipo , Ácido Pirrolidona Carboxílico/análogos & derivados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transgenes , Alas de Animales/anatomía & histología , Alas de Animales/citología , Alas de Animales/crecimiento & desarrollo
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