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1.
Elife ; 132024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38271217

RESUMO

The ratio between κ and λ light chain (LC)-expressing B cells varies considerably between species. We recently identified Kinase D-interacting substrate of 220 kDa (Kidins220) as an interaction partner of the BCR. In vivo ablation of Kidins220 in B cells resulted in a marked reduction of λLC-expressing B cells. Kidins220 knockout B cells fail to open and recombine the genes of the Igl locus, even in genetic scenarios where the Igk genes cannot be rearranged or where the κLC confers autoreactivity. Igk gene recombination and expression in Kidins220-deficient B cells is normal. Kidins220 regulates the development of λLC B cells by enhancing the survival of developing B cells and thereby extending the time-window in which the Igl locus opens and the genes are rearranged and transcribed. Further, our data suggest that Kidins220 guarantees optimal pre-BCR and BCR signaling to induce Igl locus opening and gene recombination during B cell development and receptor editing.


Assuntos
Linfócitos B , Transdução de Sinais , Linfócitos B/metabolismo
2.
Blood Adv ; 7(24): 7525-7538, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-37639313

RESUMO

Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through the activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong antileukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow cells. This antileukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.


Assuntos
Aminoácidos de Cadeia Ramificada , Leucemia Mieloide Aguda , Receptores Acoplados a Proteínas G , Animais , Humanos , Camundongos , Aminoácidos de Cadeia Ramificada/uso terapêutico , Transportador 1 de Aminoácidos Neutros Grandes/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , NF-kappa B/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
3.
Cell Rep ; 41(8): 111677, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36417858

RESUMO

Adult hematopoietic stem and progenitor cells (HSPCs) respond directly to inflammation and infection, causing both acute and persistent changes to quiescence, mobilization, and differentiation. Here we show that murine fetal HSPCs respond to prenatal inflammation in utero and that the fetal response shapes postnatal hematopoiesis and immune cell function. Heterogeneous fetal HSPCs show divergent responses to maternal immune activation (MIA), including changes in quiescence, expansion, and lineage-biased output. Single-cell transcriptomic analysis of fetal HSPCs in response to MIA reveals specific upregulation of inflammatory gene profiles in discrete, transient hematopoietic stem cell (HSC) populations that propagate expansion of lymphoid-biased progenitors. Beyond fetal development, MIA causes the inappropriate expansion and persistence of fetal lymphoid-biased progenitors postnatally, concomitant with increased cellularity and hyperresponsiveness of fetal-derived innate-like lymphocytes. Our investigation demonstrates how inflammation in utero can direct the output and function of fetal-derived immune cells by reshaping fetal HSC establishment.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Gravidez , Feminino , Camundongos , Animais , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Feto , Inflamação/metabolismo , Desenvolvimento Fetal
5.
Nat Cell Biol ; 24(7): 1038-1048, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35725769

RESUMO

Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape of highly purified human bone marrow HSCs displaying varying degrees of dormancy. We identify the orphan receptor GPRC5C, which enriches for dormant human HSCs. GPRC5C is also essential for HSC function, as demonstrated by genetic loss- and gain-of-function analyses. Through structural modelling and biochemical assays, we show that hyaluronic acid, a bone marrow extracellular matrix component, preserves dormancy through GPRC5C. We identify the hyaluronic acid-GPRC5C signalling axis controlling the state of dormancy in mouse and human HSCs.


Assuntos
Células-Tronco Hematopoéticas , Ácido Hialurônico , Animais , Medula Óssea , Hematopoese , Humanos , Camundongos , Transdução de Sinais
6.
Cell Stem Cell ; 29(1): 131-148.e10, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34706256

RESUMO

Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.


Assuntos
Células-Tronco Hematopoéticas , Tretinoína , Diferenciação Celular , Ácido Retinoico 4 Hidroxilase/genética , Transdução de Sinais , Tretinoína/farmacologia
7.
Blood ; 137(23): 3218-3224, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33754628

RESUMO

Hematopoietic stem cells (HSCs) and distinct multipotent progenitor (MPP) populations (MPP1-4) contained within the Lin-Sca-1+c-Kit+ (LSK) compartment have previously been identified using diverse surface-marker panels. Here, we phenotypically define and functionally characterize MPP5 (LSK CD34+CD135-CD48-CD150-). Upon transplantation, MPP5 supports initial emergency myelopoiesis followed by stable contribution to the lymphoid lineage. MPP5, capable of generating MPP1-4 but not HSCs, represents a dynamic and versatile component of the MPP network. To characterize all hematopoietic stem and progenitor cells, we performed RNA-sequencing (RNA-seq) analysis to identify specific transcriptomic landscapes of HSCs and MPP1-5. This was complemented by single-cell RNA-seq analysis of LSK cells to establish the differentiation trajectories from HSCs to MPP1-5. In agreement with functional reconstitution activity, MPP5 is located immediately downstream of HSCs but upstream of the more committed MPP2-4. This study provides a comprehensive analysis of the LSK compartment, focusing on the functional and molecular characteristics of the newly defined MPP5 subset.


Assuntos
Antígenos CD/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Multipotentes/metabolismo , Animais , Camundongos
8.
Sci Rep ; 10(1): 10940, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616830

RESUMO

Macroautophagy, the degradation of cytoplasmic content by lysosomal fusion, is an evolutionary conserved process promoting homeostasis and intracellular defence. Macroautophagy is initiated primarily by a complex containing ULK1 or ULK2 (two paralogs of the yeast Atg1 protein). To understand the differences between ULK1 and ULK2, we compared the human ULK1 and ULK2 proteins and their regulation. Despite the similarity in their enzymatic domain, we found that ULK1 and ULK2 have major differences in their autophagy-related interactors and their post-translational and transcriptional regulators. We identified 18 ULK1-specific and 7 ULK2-specific protein motifs serving as different interaction interfaces. We found that interactors of ULK1 and ULK2 all have different tissue-specific expressions partially contributing to diverse and ULK-specific interaction networks in various tissues. We identified three ULK1-specific and one ULK2-specific transcription factor binding sites, and eight sites shared by the regulatory region of both genes. Importantly, we found that both their post-translational and transcriptional regulators are involved in distinct biological processes-suggesting separate functions for ULK1 and ULK2. Unravelling differences between ULK1 and ULK2 could lead to a better understanding of how ULK-type specific dysregulation affects autophagy and other cellular processes that have been implicated in diseases such as inflammatory bowel disease and cancer.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Biologia Computacional/métodos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/química , Proteínas Relacionadas à Autofagia/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Lisossomos , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Proteínas Serina-Treonina Quinases/química
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