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1.
Cell ; 187(12): 3056-3071.e17, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848678

RESUMO

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.


Assuntos
Homeostase , Mucosa Intestinal , Receptores Acoplados a Proteínas G , Regeneração , Células-Tronco , Animais , Células-Tronco/metabolismo , Células-Tronco/citologia , Camundongos , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Intestinos/citologia , Diferenciação Celular , Camundongos Endogâmicos C57BL , Células Epiteliais/metabolismo , Análise de Célula Única , Masculino
2.
Cell Mol Gastroenterol Hepatol ; 11(4): 1119-1138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33249238

RESUMO

BACKGROUND & AIMS: Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed. METHODS: We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival. RESULTS: In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. CONCLUSIONS: Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.


Assuntos
Medula Óssea/patologia , Colite/patologia , Células-Tronco Hematopoéticas/patologia , Histamina/metabolismo , Histidina Descarboxilase/fisiologia , Inflamação/patologia , Intestinos/patologia , Células Mieloides/patologia , Animais , Medula Óssea/imunologia , Medula Óssea/metabolismo , Colite/etiologia , Colite/metabolismo , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Intestinos/imunologia , Intestinos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Transdução de Sinais
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