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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.
bioRxiv ; 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37873470

RESUMO

The Mechanism of Action (MoA) of a drug is generally represented as a small, non-tissue-specific repertoire of high-affinity binding targets. Yet, drug activity and polypharmacology are increasingly associated with a broad range of off-target and tissue-specific effector proteins. To address this challenge, we have implemented an efficient integrative experimental and computational framework leveraging the systematic generation and analysis of drug perturbational profiles representing >700 FDA-approved and experimental oncology drugs, in cell lines selected as high-fidelity models of 23 aggressive tumor subtypes. Protein activity-based analyses revealed highly reproducible, drug-mediated modulation of tissue-specific targets, leading to generation of a proteome-wide polypharmacology map, characterization of MoA-related drug clusters and off-target effects, and identification and experimental validation of novel, tissue-specific inhibitors of undruggable oncoproteins. The proposed framework, which is easily extended to elucidating the MoA of novel small-molecule libraries, could help support more systematic and quantitative approaches to precision oncology.

3.
Cell Stem Cell ; 21(6): 747-760.e7, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198940

RESUMO

Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc+ myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H2 receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H2 agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis.


Assuntos
Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Histamina/metabolismo , Células Mieloides/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Transplante de Medula Óssea , Citometria de Fluxo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Células Mieloides/efeitos dos fármacos
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