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1.
NPJ Genom Med ; 7(1): 43, 2022 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-35869090

RESUMEN

Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

2.
Cell Rep ; 29(2): 270-282.e5, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31597091

RESUMEN

Accumulation of visceral (VIS) is a predictor of metabolic disorders and insulin resistance. This is due in part to the limited capacity of VIS fat to buffer lipids allowing them to deposit in insulin-sensitive tissues. Mechanisms underlying selective hypertrophic growth and tissue remodeling properties of VIS fat are not well understood. We identified subsets of adipose progenitors (APs) unique to VIS fat with differential Cd34 expression and adipogenic capacity. VIS low (Cd34 low) APs are adipogenic, whereas VIS high (Cd34 high) APs are not. Furthermore, VIS high APs inhibit adipogenic differentiation of SUB and VIS low APs in vitro through the secretion of soluble inhibitory factor(s). The number of VIS high APs increased with adipose tissue expansion, and their abundance in vivo caused hypertrophic growth, fibrosis, inflammation, and metabolic dysfunction. This study unveils the presence of APs unique to VIS fat involved in the paracrine regulation of adipogenesis and tissue remodeling.


Asunto(s)
Antígenos CD34/metabolismo , Grasa Intraabdominal/citología , Comunicación Paracrina , Transducción de Señal , Células Madre/metabolismo , Adipogénesis/efectos de los fármacos , Tejido Adiposo Blanco/citología , Animales , Proteína Morfogenética Ósea 4/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Masculino , Ratones Endogámicos C57BL , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Comunicación Paracrina/efectos de los fármacos , Fenotipo , Rosiglitazona/farmacología , Transducción de Señal/efectos de los fármacos , Solubilidad , Células Madre/efectos de los fármacos , Aumento de Peso/efectos de los fármacos
3.
Cell Rep ; 25(7): 1708-1717.e5, 2018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-30428342

RESUMEN

Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues.


Asunto(s)
Adipocitos/citología , Tejido Adiposo/metabolismo , Autofagia , Resistencia a la Insulina , Peróxidos Lipídicos/metabolismo , Hígado/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Adiposidad , Animales , Proteínas Relacionadas con la Autofagia/metabolismo , Composición Corporal , Peso Corporal , Humanos , Inflamación/patología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Lipoproteínas HDL/metabolismo , Ratones Noqueados , Mitocondrias/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo
4.
FEBS Lett ; 581(9): 1865-70, 2007 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-17434491

RESUMEN

Lens regeneration in adult newts is possible by transdifferentiation of the pigment epithelial cells (PECs) of the dorsal iris. The same cells in the ventral iris are not capable of such a process. To understand this difference in regenerative competency, we examined gene expression of 373 genes in the intact dorsal and ventral irises as well as in irises during the process of lens regeneration. We found similar signatures of gene expression in dorsal and ventral with several cases of even higher levels in the ventral iris. Such transcriptional activity in the regeneration-incompetent ventral iris was unexpected and calls for a revision of our views about mechanisms of lens regeneration induction.


Asunto(s)
Iris/metabolismo , Cristalino/fisiología , Regeneración/genética , Salamandridae/genética , Salamandridae/fisiología , Animales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Cristalino/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa
5.
Cell Transplant ; 25(9): 1591-1607, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27165370

RESUMEN

The development of cell- and gene-based strategies for regenerative medicine offers a therapeutic option for the repair and potential regeneration of damaged cardiac tissue post-myocardial infarction (MI). Human umbilical cord subepithelial cell-derived stem cells (hUC-SECs), human bone marrow-derived mesenchymal stem cells (hBM-MSCs), and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all derived from human tissue, have been shown to have in vitro and in vivo therapeutic potential. Additionally, S100a1, VEGF165, and stromal-derived factor-1α (SDF-1α) genes all have the potential to improve cardiac function and/or effect adverse remodeling. In this study, we compared the therapeutic potential of hBM-MSCs, hUC-SECs, and hiPSC-CMs along with plasmid-based genes to evaluate the in vivo potential of intramyocardially injected biologics to enhance cardiac function in a mouse MI model. Human cells derived from various tissue types were expanded under hypoxic conditions and injected intramyocardially into mice that had undergone left anterior descending (LAD) artery ligation. Similarly, plasmids were also injected into three groups of mice after LAD ligation. Seven experimental groups were studied in total: (1) control (saline), (2) hBM-MSCs, (3) hiPSC-CMs, (4) hUC-SECs, (5) S100a1 plasmid, (6) VEGF165 plasmid, and (7) SDF-1α plasmid. We evaluated echocardiography, hemodynamic catheterization measurements, and histology at 4 and 12 weeks post-biologic injection. Significant improvement was observed in cardiac function and contractility in hiPSC-CM and S100a1 groups and a significant reduction in left ventricle scar within the hUC-SEC group and a slight improvement in the SDF-1α and VEGF165 groups compared to the control group. These results demonstrate the potential for new biologic therapies to reduce scar burden and improve contractile function.


Asunto(s)
Terapia Biológica/métodos , Infarto del Miocardio/terapia , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Terapia Genética/métodos , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/fisiología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología
6.
PLoS One ; 7(12): e52375, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23300656

RESUMEN

The inability to functionally repair tissues that are lost as a consequence of disease or injury remains a significant challenge for regenerative medicine. The molecular and cellular processes involved in complete restoration of tissue architecture and function are expected to be complex and remain largely unknown. Unlike humans, certain salamanders can completely regenerate injured tissues and lost appendages without scar formation. A parsimonious hypothesis would predict that all of these regenerative activities are regulated, at least in part, by a common set of genes. To test this hypothesis and identify genes that might control conserved regenerative processes, we performed a comprehensive microarray analysis of the early regenerative response in five regeneration-competent tissues from the newt Notophthalmus viridescens. Consistent with this hypothesis, we established a molecular signature for regeneration that consists of common genes or gene family members that exhibit dynamic differential regulation during regeneration in multiple tissue types. These genes include members of the matrix metalloproteinase family and its regulators, extracellular matrix components, genes involved in controlling cytoskeleton dynamics, and a variety of immune response factors. Gene Ontology term enrichment analysis validated and supported their functional activities in conserved regenerative processes. Surprisingly, dendrogram clustering and RadViz classification also revealed that each regenerative tissue had its own unique temporal expression profile, pointing to an inherent tissue-specific regenerative gene program. These new findings demand a reconsideration of how we conceptualize regenerative processes and how we devise new strategies for regenerative medicine.


Asunto(s)
Regeneración , Análisis de Matrices Tisulares , Animales , Citoesqueleto/metabolismo , Inmunidad , Notophthalmus viridescens/inmunología , Notophthalmus viridescens/fisiología , Especificidad de Órganos , Reproducibilidad de los Resultados , Transducción de Señal
7.
Dev Dyn ; 235(3): 606-16, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16372340

RESUMEN

Matrix metalloproteinase (MMP) activity is important for newt limb regeneration. In most biological processes that require MMP function, MMP activity is tightly controlled by a variety of mechanisms, including the coexpression of natural inhibitors. Here, we show that gene expression of one such inhibitor, tissue inhibitor of metalloproteinase 1 (NvTIMP1), is upregulated during the wound healing and dedifferentiation stages of regeneration when several MMPs are at their maximal expression levels. Newt MMPs and NvTIMP1 also exhibit similar spatial expression patterns during the early stages of limb regeneration. NvTIMP1 inhibits the proteolytic activity of regeneration-related newt MMPs and, like human TIMP1, can induce a weak mitogenic response in certain cell types. These results suggest that NvTIMP1 may be functioning primarily to maintain optimal levels of MMP activity during the early stages of limb regeneration, while possibly serving a secondary role as a mitogen.


Asunto(s)
Extremidades/fisiología , Metaloproteasas/metabolismo , Regeneración , Salamandridae/fisiología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Secuencia de Aminoácidos , Animales , Regulación del Desarrollo de la Expresión Génica , Metaloproteasas/antagonistas & inhibidores , Datos de Secuencia Molecular , Regeneración/genética , Salamandridae/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Regulación hacia Arriba , Cicatrización de Heridas/genética
8.
Dev Biol ; 299(1): 257-71, 2006 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-16949563

RESUMEN

Newts have the remarkable ability to regenerate lost appendages including their forelimbs, hindlimbs, and tails. Following amputation of an appendage, the wound is rapidly closed by the migration of epithelial cells from the proximal epidermis. Internal cells just proximal to the amputation plane begin to dedifferentiate to form a pool of proliferating progenitor cells known as the regeneration blastema. We show that dedifferentiation of internal appendage cells can be initiated in the absence of amputation by applying an electric field sufficient to induce cellular electroporation, but not necrosis or apoptosis. The time course for dedifferentiation following electroporation is similar to that observed following amputation with evidence of dedifferentiation beginning at about 5 days postelectroporation and continuing for 2 to 3 weeks. Microarray analyses, real-time RT-PCR, and in situ hybridization show that changes in early gene expression are similar following amputation or electroporation. We conclude that the application of an electric field sufficient to induce transient electroporation of cell membranes induces a dedifferentiation response that is virtually indistinguishable from the response that occurs following amputation of newt appendages. This discovery allows dedifferentiation to be studied in the absence of wound healing and may aid in identifying genes required for cellular plasticity.


Asunto(s)
Diferenciación Celular , Electroporación/métodos , Miembro Anterior/citología , Miembro Posterior/citología , Salamandridae/fisiología , Amputación Quirúrgica , Animales , Ciclo Celular , Muerte Celular , Miembro Anterior/fisiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Regeneración , Cola (estructura animal)/citología , Factores de Tiempo
9.
Dev Biol ; 279(1): 86-98, 2005 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-15708560

RESUMEN

Newts regenerate lost limbs through a complex process involving dedifferentiation, migration, proliferation, and redifferentiation of cells proximal to the amputation plane. To identify the genes controlling these cellular events, we performed a differential display analysis between regenerating and nonregenerating limbs from the newt Notophthalmus viridescens. This analysis, coupled with a direct cloning approach, identified a previously unknown Notophthalmus collagenase gene (nCol) and three known matrix metalloproteinase (MMP) genes, MMP3/10a, MMP3/10b, and MMP9, all of which are upregulated within hours of limb amputation. MMP3/10b exhibits the highest and most ubiquitous expression and appears to account for the majority of the proteolytic activity in the limb as measured by gel zymography. By testing purified recombinant MMP proteins against potential substrates, we show that nCol is a true collagenase, MMP9 is a gelatinase, MMP3/10a is a stromelysin, and MMP3/10b has an unusually broad substrate profile, acting both as a stromelysin and noncanonical collagenase. Exposure of regenerating limbs to the synthetic MMP inhibitor GM6001 produces either dwarfed, malformed limb regenerates or limb stumps with distal scars. These data suggest that MMPs are required for normal newt limb regeneration and that MMPs function, in part, to prevent scar formation during the regenerative process.


Asunto(s)
Extremidades/fisiología , Regulación del Desarrollo de la Expresión Génica , Metaloproteinasas de la Matriz/metabolismo , Notophthalmus viridescens/embriología , Regeneración , Secuencia de Aminoácidos , Animales , Diferenciación Celular , División Celular , Secuencia Conservada , Cartilla de ADN , Embrión no Mamífero/fisiología , Cinética , Metaloproteinasas de la Matriz/genética , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Alineación de Secuencia , Homología de Secuencia de Aminoácido
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