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1.
Dev Cell ; 58(24): 2914-2929.e7, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38113852

RESUMO

Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.


Assuntos
Mucosa Intestinal , Intestinos , Camundongos , Animais , Células-Tronco , Fenótipo , Inflamação
2.
Sci Rep ; 12(1): 22266, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36564544

RESUMO

Treatment of myelodysplastic syndromes includes the administration of the hypomethylating agent decitabine. An early platelet response in decitabine-treated myelodysplastic syndrome patients is a predictor of overall survival. The effect of decitabine on megakaryocytes and the bone marrow, however, is understudied. We show that an early platelet increment was not detectable in healthy mice during decitabine treatment. Analyses of bone marrow sections revealed vessels with dilated lumina, decreased cellularity, but increased number of red blood cells and the presence of (pro)platelet-like particles. Taken together, decitabine treatment of healthy mice does not induce an early platelet increment, but affects the bone marrow.


Assuntos
Azacitidina , Síndromes Mielodisplásicas , Animais , Camundongos , Decitabina/farmacologia , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Plaquetas , Megacariócitos , Resultado do Tratamento
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