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1.
Cell Physiol Biochem ; 53(5): 887-909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749350

RESUMO

Over the past years, the benefits of stem cell therapy approach for treatment of the cardiovascular diseases have been shown through the rebuilding of new cardiomyocytes and blood vessels. while a successful regeneration of the myocardium has been proven on the animal models of acute myocardial injuries resulted from the stem cells transplantation, no significant long-term regenerative with autologous stem cell therapy in patients with acute myocardial infarction have been reported based on recent meta-analyses. It seems that the inflammatory microenvironment of acute myocardial infarction has an inhibitory effect on the stem cells potential for regenerating the injured myocardium. Secretion of critical cytokines with pro-inflammatory properties including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 as well as induction of hypoxic condition and finally formation of cytotoxic elements cause the cellular death and hinder the stem cells proliferation and differentiation. Based on the evidence, application of some approaches like co-delivery of mesenchymal stem cells with the other useful cells, using the stem cells derived productions, administration of preconditioned and modified cells, and also using the anti-inflammatory agents besides the cell therapy are hypothesized as the primary developed safe and practical approaches for decreasing destructive effects of the inflammation on the implanted stem/progenitor cells. In this review, we critically discuss the quiddity of the inflammatory microenvironment and its promoted mechanisms as the main elements to hinder the efficacy of stem cell therapy in the cases of acute myocardial infarction. Also, we finally propose some applied solutions to the problem of cardiac regeneration with stem cells therapy.


Assuntos
Infarto do Miocárdio/terapia , Transplante de Células-Tronco , Terapia Baseada em Transplante de Células e Tecidos , Microambiente Celular , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Coração/fisiologia , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Regeneração/fisiologia , Células-Tronco/citologia , Células-Tronco/metabolismo
2.
Nature ; 574(7779): 538-542, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645727

RESUMO

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.


Assuntos
Células Clonais/citologia , Células Clonais/patologia , Fibrose/genética , Fibrose/patologia , Fígado/citologia , Fígado/metabolismo , Mutação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Células Clonais/metabolismo , Análise Mutacional de DNA , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Filogenia , Células-Tronco/citologia , Células-Tronco/metabolismo , Células-Tronco/patologia
3.
Nature ; 574(7779): 532-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645730

RESUMO

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismo
4.
Genome Biol ; 20(1): 192, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500663

RESUMO

We introduce CUT&RUNTools as a flexible, general pipeline for facilitating the identification of chromatin-associated protein binding and genomic footprinting analysis from antibody-targeted CUT&RUN primary cleavage data. CUT&RUNTools extracts endonuclease cut site information from sequences of short-read fragments and produces single-locus binding estimates, aggregate motif footprints, and informative visualizations to support the high-resolution mapping capability of CUT&RUN. CUT&RUNTools is available at https://bitbucket.org/qzhudfci/cutruntools/ .


Assuntos
Pegadas de Proteínas/métodos , Software , Cromatina/metabolismo , Endonucleases , Fator de Transcrição GATA1/análise , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , Células-Tronco/metabolismo
5.
J Agric Food Chem ; 67(41): 11464-11473, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532211

RESUMO

The intestinal epithelium is derived from intestinal stem cells (ISCs) and has direct contact with nutrients and toxins. However, whether methionine (Met) or a methionine hydroxyl analogue (2-hydroxy-4-(methylthio)butanoic acid (HMB)) can alleviate deoxynivalenol (DON)-induced intestinal injury remains unknown. Mice were treated orally with Met or HMB on days 1-11 and with DON on days 4-8. On day 12, the mice were sacrificed, and the jejunum was collected for crypt isolation and culture. Mouse enteroids were treated with DON and Met or HMB ex vivo. The results showed that Met and HMB increased the average daily feed intake and average daily gain of the mice. Met and HMB also improved the jejunal structure and barrier integrity and promoted ISC expansion, as indicated by the increased enteroid formation efficiency and area, under DON-induced injury conditions. In addition, DON-induced decreases in ISC activity were rescued Wnt/ß-catenin signaling reactivation by Met or HMB in vivo and ex vivo. Collectively, our findings reveal that Met and HMB alleviated DON-induced intestinal injury by improving ISC expansion and reactivating Wnt/ß-catenin signaling. Our study thus provides a nutritional intervention for intestinal diseases involving Wnt/ß-catenin signaling.


Assuntos
Enteropatias/tratamento farmacológico , Metionina/análogos & derivados , Metionina/administração & dosagem , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Tricotecenos/toxicidade , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Enteropatias/genética , Enteropatias/metabolismo , Enteropatias/fisiopatologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Células-Tronco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
6.
J Agric Food Chem ; 67(34): 9510-9521, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31382738

RESUMO

Glutamate (Glu) is a critical nutritional regulator of intestinal epithelial homeostasis. In addition, intestinal stem cells (ISCs) at crypt bases are known to play important roles in maintaining the renewal and homeostasis of the intestinal epithelium, and the aspects of communication between Glu and ISCs are still unknown. Here, we identify Glu and mammalian target of rapamycin complex 1 (mTORC1) as essential regulators of ISC expansion. The results showed that extracellular Glu promoted ISC expansion, indicated by increased intestinal organoid forming efficiency and budding efficiency as well as cell proliferation marker Ki67 immunofluorescence and differentiation marker Keratin 20 (KRT20) expression. Moreover, the insulin receptor (IR) mediating phosphorylation of the insulin receptor substrate (IRS) and downstream signaling phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway was involved in this response in ISCs. As expected, Glu-induced mTORC1 signaling activation was observed in the intestinal porcine enterocyte cell line (IPEC-J2), and Glu activated the PI3K/Akt/mTORC1 pathway. Accordingly, PI3K inhibition partially suppressed Glu-induced mTORC1 activation. In addition, Glu increased the phosphorylation levels of IR and IRS, and inhibiting IR downregulated the IRS/PI3K/Akt pathway. Collectively, our findings first indicate that extracellular Glu activates mTORC1 via the IR/IRS/PI3K/Akt pathway and stimulates ISC expansion, providing a new perspective for regulating the growth and health of the intestinal epithelium.


Assuntos
Ácido Glutâmico/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Mucosa Intestinal/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Células-Tronco/metabolismo , Animais , Proteínas Substratos do Receptor de Insulina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de Insulina/genética , Transdução de Sinais , Suínos
7.
Int J Nanomedicine ; 14: 4849-4866, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308662

RESUMO

Stem cells possess a promising potential in the clinical field. The application and effective delivery of stem cells to the desired target organ or site of injury plays an important role. This review describes strategies on understanding the effective delivery of stem cells labeled with superparamagnetic iron oxide nanoparticles (SPION) using an external magnet to enhance stem cell migration in vivo and in vitro. Fourteen total publications among 174 articles were selected. Stem cell type, SPION characteristics, labeling time, and magnetic force in vivo are considered important factors affecting the effective delivery of stem cells to the homing site. Most papers reported that the efficiency was increased when magnet is applied compared to those without. Ten studies analyzed the homing competency of SPION-labeled MSCs in vitro by observing the migration of the cell toward the external magnet. In cell-based experiments, the mechanism of magnetic attraction, the kind of nanoparticles, and various stem cells were studied well. Meta-analysis has shown the mean size of nanoparticles and degree of recovery or regeneration of damaged target organs upon in vivo studies. This strategy may provide a guideline for designing studies involving stem cell homing and further expand stem cell.


Assuntos
Magnetismo/métodos , Nanopartículas de Magnetita/química , Coloração e Rotulagem , Células-Tronco/metabolismo , Animais , Movimento Celular , Humanos , Hidrodinâmica , Tamanho da Partícula , Células-Tronco/citologia
8.
Cytogenet Genome Res ; 158(3): 133-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31272101

RESUMO

Bone morphogenetic protein 2 (BMP2) can mediate the signaling of R-Smads and regulate different biological functions, including adipocyte differentiation. Long noncoding RNAs (lncRNAs) can be involved in many important biological processes, including fat metabolism, as miRNA sponges. This study aimed to investigate the molecular mechanism of fat deposition and to provide useful information for the prevention and treatment of lipid-related diseases. lncRNA sequencing was performed to compare and analyze, for the first time, the expression of lncRNAs in BMP2-induced and non-BMP2-induced preadipocytes from Junmu1 pigs. In addition, functional annotation and enrichment analysis of differentially expressed lncRNA target genes were carried out. lncRNAs and mRNAs were compared and analyzed. lncRNAs were identified that may regulate adipogenesis and lipid metabolism. The results give a theoretical basis for further studies on fat deposition mechanisms and provide potential therapeutic targets for metabolic diseases.


Assuntos
Adipócitos/efeitos dos fármacos , Proteína Morfogenética Óssea 2/farmacologia , Diferenciação Celular/efeitos dos fármacos , RNA Longo não Codificante/análise , Células-Tronco/efeitos dos fármacos , Suínos/genética , Transcriptoma/genética , Adipócitos/citologia , Adipócitos/metabolismo , Animais , RNA Longo não Codificante/genética , Análise de Sequência de RNA , Células-Tronco/citologia , Células-Tronco/metabolismo , Triglicerídeos/metabolismo
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 425-429, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282341

RESUMO

Human optic nerve injury and its associated neurodegenerative diseases are often followed by permanent vision loss.Stem cell therapy has long been considered a promising mode to treat retinal degenerative diseases.Recent studies revealed that there are silent retinal stem cells in the eyes of mammals and even humans.These stem cells can be activated again under certain conditions and differentiate into retinal neurons to repair the damaged retina.Wnt signaling pathway plays a crucial role in conducting growth-stimulating signals and regulates cell proliferation,differentiation and apoptosis.This article review the regulatory effect of Wnt signaling pathway on stem cells-based retinal regeneration and the sources of retinal stem cells.


Assuntos
Regeneração , Retina/crescimento & desenvolvimento , Células-Tronco/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Humanos
10.
Cancer Causes Control ; 30(10): 1103-1111, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352658

RESUMO

PURPOSE: High mammographic breast density is a strong, well-established breast cancer risk factor. Whether stem cells may explain high breast cancer risk in dense breasts is unknown. We investigated the association between breast density and breast cancer risk by the status of stem cell markers CD44, CD24, and ALDH1A1 in the tumor. METHODS: We included 223 women with primary invasive or in situ breast cancer and 399 age-matched controls from Mayo Clinic Mammography Study. Percent breast density (PD), absolute dense area (DA), and non-dense area (NDA) were assessed using computer-assisted thresholding technique. Immunohistochemical analysis of the markers was performed on tumor tissue microarrays according to a standard protocol. We used polytomous logistic regression to quantify the associations of breast density measures with breast cancer risk across marker-defined tumor subtypes. RESULTS: Of the 223 cancers in the study, 182 were positive for CD44, 83 for CD24 and 52 for ALDH1A1. Associations of PD were not significantly different across t marker-defined subtypes (51% + vs. 11-25%: OR 2.83, 95% CI 1.49-5.37 for CD44+ vs. OR 1.87, 95% CI 0.47-7.51 for CD44-, p-heterogeneity = 0.66; OR 2.80, 95% CI 1.27-6.18 for CD24+ vs. OR 2.44, 95% CI 1.14-5.22 for CD24-, p-heterogeneity = 0.61; OR 3.04, 95% CI 1.14-8.10 for ALDH1A1+ vs. OR 2.57. 95% CI 1.30-5.08 for ALDH1A1-, p-heterogeneity = 0.94). Positive associations of DA and inverse associations of NDA with breast cancer risk were similar across marker-defined subtypes. CONCLUSIONS: We found no evidence of differential associations of breast density with breast cancer risk by the status of stem cell markers. Further studies in larger study populations are warranted to confirm these associations.


Assuntos
Biomarcadores Tumorais/metabolismo , Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Mamografia , Idoso , Mama/diagnóstico por imagem , Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Células-Tronco/metabolismo
11.
Nat Commun ; 10(1): 2988, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278345

RESUMO

Precise control of stem cell (SC) proliferation ensures tissue homeostasis. In the Drosophila intestine, injury-induced regeneration involves initial activation of intestinal SC (ISC) proliferation and subsequent return to quiescence. These two phases of the regenerative response are controlled by differential availability of the BMP type I receptor Thickveins (Tkv), yet how its expression is dynamically regulated remains unclear. Here we show that during homeostasis, the E3 ubiquitin ligase Highwire and the ubiquitin-proteasome system maintain low Tkv protein expression. After ISC activation, Tkv is stabilized by proteasome inhibition and undergoes endocytosis due to the induction of the nucleoside diphosphate kinase Abnormal Wing Disc (AWD). Tkv internalization is required for the activation of the Smad protein Mad, and for the return to quiescence after a regenerative episode. Our data provide insight into the mechanisms ensuring tissue homeostasis by dynamic control of somatic stem cell activity.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Drosophila/metabolismo , Núcleosídeo-Difosfato Quinase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Drosophila melanogaster , Feminino , Homeostase/fisiologia , Intestinos/citologia , Modelos Animais , Proteínas do Tecido Nervoso/metabolismo , Regeneração , Fatores de Transcrição/metabolismo
12.
Cell Mol Life Sci ; 76(20): 4043-4070, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31317205

RESUMO

Stem cells give rise to all cells and build the tissue structures in our body, and heterogeneity and plasticity are the hallmarks of stem cells. Epigenetic modification, which is associated with niche signals, determines stem cell differentiation and somatic cell reprogramming. Stem cells play a critical role in the development of tumors and are capable of generating 3D organoids. Understanding the properties of stem cells will improve our capacity to maintain tissue homeostasis. Dissecting epigenetic regulation could be helpful for achieving efficient cell reprograming and for developing new drugs for cancer treatment. Stem cell-derived organoids open up new avenues for modeling human diseases and for regenerative medicine. Nevertheless, in addition to the achievements in stem cell research, many challenges still need to be overcome for stem cells to have versatile application in clinics.


Assuntos
Epigênese Genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Organoides/metabolismo , Células-Tronco/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Transdiferenciação Celular , Reprogramação Celular , Transição Epitelial-Mesenquimal , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas/patologia , Organoides/patologia , Medicina Regenerativa/métodos , Nicho de Células-Tronco/genética , Transplante de Células-Tronco/métodos , Células-Tronco/classificação , Células-Tronco/citologia
13.
Mol Biol (Mosk) ; 53(3): 497-501, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184615

RESUMO

Homeodomain transcription factors play a significant role in adipocyte differentiation. The role of Pbx1 and Prep1, proteins of the TALE family (the three amino acid loop extension), was previously established in adipocyte differentiation of mesenchymal stromal cells and 3T3-L1 cell line. In this study, with the use of RNA interference technology we show that another transcription factor from the same family, Meis1, which is a core protein of mature cardiomyocytes, represses adipogenesis to a greater degree than its paralog Meis2. A number of Meis target genes, markers of adipocytes, are identified. This may indicate the transcriptional mechanism of the effect of Meis1 on the adipocyte differentiation of mouse preadipocytes.


Assuntos
Adipócitos/citologia , Diferenciação Celular , Proteína Meis1/metabolismo , Miócitos Cardíacos/metabolismo , Adipócitos/metabolismo , Animais , Diferenciação Celular/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo
14.
Cell Biochem Funct ; 37(5): 377-384, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215681

RESUMO

Dietary vitamin A status affects energy metabolism. The present study explored the effect of all-trans retinoic acid (ATRA) on the expression levels of molecules and metabolites of brown adipocytes. Chronic ATRA treatment was initiated during the early stage (days 0-8) or late stage (days 8-12) of adipogenesis. Treatment with ATRA during the early and late stage of adipogenesis resulted in an increase in the expression level of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12, respectively, whereas expression of Pgc-1α, another gene expressed during brown adipogenesis, was unaffected by ATRA. Non-targeted metabolomic analyses indicated that the pathways related to the glucose metabolism were affected by ATRA, irrespective of the differentiation stage. Cellular levels of glucose 6-phosphate, fructose 6-phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA-treated cells on day 8, but it was lower on day 12. ATRA decreased the cellular level of aconitic acid, fumaric acid, and malic acid on day 12 but not on day 8. Furthermore, ATRA increased the expression level of Hxk2 and downregulated the expressions of G6pdh and Pfkl/Pfkp on day 8 but not on day 12. Together, the results indicate that the chronic treatment with ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism. SIGNIFICANCE OF THE STUDY: Significance of the study treatment with all-trans retinoic acid (ATRA) during the early and late stage of adipogenesis increased the expression of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12. Cellular levels of glucose 6-phosphate, fructose 6-phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA-treated cells on day 8, but it was lower on day 12. The present results indicate that ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Diferenciação Celular/efeitos dos fármacos , Metabolômica , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Tretinoína/farmacologia , Adipócitos Marrons/citologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , RNA/genética , Células-Tronco/citologia , Tretinoína/administração & dosagem
15.
Nat Cell Biol ; 21(6): 710-720, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160709

RESUMO

The capacity of stem cells to self-renew or differentiate has been attributed to distinct metabolic states. A genetic screen targeting regulators of mitochondrial dynamics revealed that mitochondrial fusion is required for the maintenance of male germline stem cells (GSCs) in Drosophila melanogaster. Depletion of Mitofusin (dMfn) or Opa1 led to dysfunctional mitochondria, activation of Target of rapamycin (TOR) and a marked accumulation of lipid droplets. Enhancement of lipid utilization by the mitochondria attenuated TOR activation and rescued the loss of GSCs that was caused by inhibition of mitochondrial fusion. Moreover, constitutive activation of the TOR-pathway target and lipogenesis factor Sterol regulatory element binding protein (SREBP) also resulted in GSC loss, whereas inhibition of SREBP rescued GSC loss triggered by depletion of dMfn. Our findings highlight a critical role for mitochondrial fusion and lipid homeostasis in GSC maintenance, providing insight into the potential impact of mitochondrial and metabolic diseases on the function of stem and/or germ cells.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Membrana/genética , Dinâmica Mitocondrial/genética , Células-Tronco/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Animais , Diferenciação Celular/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Homeostase , Metabolismo dos Lipídeos/genética , Masculino , Mitocôndrias/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genética , Nicho de Células-Tronco/genética , Células-Tronco/citologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
16.
Nat Cell Biol ; 21(7): 812-823, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235935

RESUMO

Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2+Lgr5- stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5+ cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that-in contrast to its known mitogenic activity-Rspo3 induces differentiation of basal Lgr5+ cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5+ cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori, including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3-Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration.


Assuntos
Mucosa Gástrica/metabolismo , Trombospondinas/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Autorrenovação Celular/fisiologia , Camundongos Transgênicos , Miofibroblastos/metabolismo , Organoides/citologia , Receptores Acoplados a Proteínas-G/genética , Células-Tronco/metabolismo , Estômago/efeitos dos fármacos , Trombospondinas/genética , Trombospondinas/farmacologia , Via de Sinalização Wnt/fisiologia
17.
PLoS Genet ; 15(6): e1008111, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194729

RESUMO

Signal transduction activated by Wingless/Wnt ligands directs cell proliferation and fate specification in metazoans, and its overactivation underlies the development of the vast majority of colorectal cancers. In the conventional model, the secretion and movement of Wingless to cells distant from its source of synthesis are essential for long-range signaling in tissue patterning. However, this model was upended recently by an unanticipated finding: replacement of wild-type Drosophila Wingless with a membrane-tethered form produced viable adults with largely normal external morphology, which suggested that Wingless secretion and movement are dispensable for tissue patterning. Herein, we tested this foundational principle in the adult intestine, where Wingless signaling gradients coincide with all major boundaries between compartments. We find that the critical roles of Wingless during adult intestinal development, which include regulation of target gene activation, boundary formation, stem cell proliferation, epithelial cell fate specification, muscle differentiation, gut folding, and signaling crosstalk with the Decapentaplegic pathway, are all disrupted by Wingless tethering. These findings provide new evidence that supports the requirement for the direct, long-range action of Wingless in tissue patterning, with relevance for animal development, tissue homeostasis and Wnt-driven disease.


Assuntos
Padronização Corporal/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteína Wnt1/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Drosophila melanogaster/crescimento & desenvolvimento , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Homeostase , Intestinos/crescimento & desenvolvimento , Transdução de Sinais/genética , Células-Tronco/metabolismo
18.
Cell Mol Life Sci ; 76(20): 4071-4102, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254043

RESUMO

Mammalian spermatogenesis is a highly complex multi-step process sustained by a population of mitotic germ cells with self-renewal potential known as spermatogonial stem cells (SSCs). The maintenance and regulation of SSC function are strictly dependent on a supportive niche that is composed of multiple cell types. A detailed appreciation of the molecular mechanisms underpinning SSC activity and fate is of fundamental importance for spermatogenesis and male fertility. However, different models of SSC identity and spermatogonial hierarchy have been proposed and recent studies indicate that cell populations supporting steady-state germline maintenance and regeneration following damage are distinct. Importantly, dynamic changes in niche properties may underlie the fate plasticity of spermatogonia evident during testis regeneration. While formation of spermatogenic colonies in germ-cell-depleted testis upon transplantation is a standard assay for SSCs, differentiation-primed spermatogonial fractions have transplantation potential and this assay provides readout of regenerative rather than steady-state stem cell capacity. The characterisation of spermatogonial populations with regenerative capacity is essential for the development of clinical applications aimed at restoring fertility in individuals following germline depletion by genotoxic treatments. This review will discuss regulatory mechanisms of SSCs in homeostatic and regenerative testis and the conservation of these mechanisms between rodent models and man.


Assuntos
Fertilidade/genética , Infertilidade Masculina/genética , Espermatogênese/genética , Espermatogônias/citologia , Células-Tronco/citologia , Testículo/citologia , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/terapia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Modelos Genéticos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espermatogônias/metabolismo , Nicho de Células-Tronco/genética , Células-Tronco/metabolismo , Testículo/metabolismo
19.
Biochemistry (Mosc) ; 84(3): 187-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31221057

RESUMO

Perhaps there is no more intriguing topic in modern biology than stem cells. The growing interest in stem cells is dictated by the ability of stem cells to both self-renew and differentiate, at least into several type cells. If we learn to influence these properties or reproduce them in vitro, it will be possible to effectively use stem cells or their differentiated derivatives in medicine. Fundamental knowledge of mechanisms of the self-maintenance and differentiation of stem cells is important for understanding a variety of processes - from embryogenesis to aging and oncogenic transformation. The purpose of this issue is to introduce readers to different areas in research on mammalian stem cells, including human stem cells. In the issue both review articles and research papers are presented, and the authors hope that they will be of interest for biochemists, cell biologists, and specialists in the field of biomedicine.


Assuntos
Células-Tronco/citologia , Animais , Diferenciação Celular , Humanos , Células-Tronco/metabolismo
20.
Biochemistry (Mosc) ; 84(3): 232-240, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31221061

RESUMO

Extracellular matrix (ECM) proteins fill the space between cells in multicellular organisms, contributing to the structure of organs and tissues. The mechanical properties of ECM are well studied. At present, the role of individual ECM components and the three-dimensional tissue-specific matrices in the regulation of cell functional activity, proliferation, migration, acquisition of a specialized phenotype and its maintenance is intensively studied. In this review, we described main ECM structural proteins, enzymes, and extracellular vesicles and present the data on the participation of ECM components in the regulation of stem cell differentiation and self-maintenance, as well as approaches to the modeling of stem cells microenvironment using decellularized ECM.


Assuntos
Diferenciação Celular , Matriz Extracelular/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Matriz Extracelular/química , Humanos
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