Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
2.
Cell Death Dis ; 15(4): 301, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38684650

RESUMO

Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.


Assuntos
Proteína Morfogenética Óssea 4 , Calcitriol , Proteínas de Transporte , Diferenciação Celular , Colo , Dibenzazepinas , Células Caliciformes , Fator 4 Semelhante a Kruppel , Organoides , Receptores Notch , Transdução de Sinais , Humanos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proteína Morfogenética Óssea 4/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/citologia , Colo/patologia , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Calcitriol/farmacologia , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/metabolismo , Dibenzazepinas/farmacologia , Linhagem da Célula/efeitos dos fármacos , Enterócitos/metabolismo , Enterócitos/efeitos dos fármacos , Enterócitos/citologia , Vitamina D/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA