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1.
Cell ; 187(11): 2855-2874.e19, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657603

RESUMO

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.


Assuntos
Embrião de Mamíferos , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Imageamento Tridimensional , Humanos , Embrião de Mamíferos/metabolismo , Transcriptoma/genética , Gástrula/metabolismo , Gástrula/embriologia , Transdução de Sinais , Linhagem da Célula , Perfilação da Expressão Gênica , Padronização Corporal/genética
2.
Cell ; 186(10): 2092-2110.e23, 2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37172563

RESUMO

The third and fourth weeks of gestation in primates are marked by several developmental milestones, including gastrulation and the formation of organ primordia. However, our understanding of this period is limited due to restricted access to in vivo embryos. To address this gap, we developed an embedded 3D culture system that allows for the extended ex utero culture of cynomolgus monkey embryos for up to 25 days post-fertilization. Morphological, histological, and single-cell RNA-sequencing analyses demonstrate that ex utero cultured monkey embryos largely recapitulated key events of in vivo development. With this platform, we were able to delineate lineage trajectories and genetic programs involved in neural induction, lateral plate mesoderm differentiation, yolk sac hematopoiesis, primitive gut, and primordial germ-cell-like cell development in monkeys. Our embedded 3D culture system provides a robust and reproducible platform for growing monkey embryos from blastocysts to early organogenesis and studying primate embryogenesis ex utero.


Assuntos
Embrião de Mamíferos , Desenvolvimento Embrionário , Animais , Macaca fascicularis , Blastocisto , Organogênese , Primatas
3.
Cell ; 186(18): 3776-3792.e16, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37478861

RESUMO

In vitro stem cell models that replicate human gastrulation have been generated, but they lack the essential extraembryonic cells needed for embryonic development, morphogenesis, and patterning. Here, we describe a robust and efficient method that prompts human extended pluripotent stem cells to self-organize into embryo-like structures, termed peri-gastruloids, which encompass both embryonic (epiblast) and extraembryonic (hypoblast) tissues. Although peri-gastruloids are not viable due to the exclusion of trophoblasts, they recapitulate critical stages of human peri-gastrulation development, such as forming amniotic and yolk sac cavities, developing bilaminar and trilaminar embryonic discs, specifying primordial germ cells, initiating gastrulation, and undergoing early neurulation and organogenesis. Single-cell RNA-sequencing unveiled transcriptomic similarities between advanced human peri-gastruloids and primary peri-gastrulation cell types found in humans and non-human primates. This peri-gastruloid platform allows for further exploration beyond gastrulation and may potentially aid in the development of human fetal tissues for use in regenerative medicine.


Assuntos
Implantação do Embrião , Gastrulação , Células-Tronco Pluripotentes , Animais , Feminino , Humanos , Gravidez , Diferenciação Celular , Embrião de Mamíferos , Desenvolvimento Embrionário , Organogênese , Células-Tronco Pluripotentes/metabolismo , Primatas
4.
Annu Rev Biochem ; 87: 809-837, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29596003

RESUMO

To maintain an asymmetric distribution of ions across membranes, protein pumps displace ions against their concentration gradient by using chemical energy. Here, we describe a functionally analogous but topologically opposite process that applies to the lipid transfer protein (LTP) oxysterol-binding protein (OSBP). This multidomain protein exchanges cholesterol for the phosphoinositide phosphatidylinositol 4-phosphate [PI(4)P] between two apposed membranes. Because of the subsequent hydrolysis of PI(4)P, this counterexchange is irreversible and contributes to the establishment of a cholesterol gradient along organelles of the secretory pathway. The facts that some natural anti-cancer molecules block OSBP and that many viruses hijack the OSBP cycle for the formation of intracellular replication organelles highlight the importance and potency of OSBP-mediated lipid exchange. The architecture of some LTPs is similar to that of OSBP, suggesting that the principles of the OSBP cycle-burning PI(4)P for the vectorial transfer of another lipid-might be general.


Assuntos
Colesterol/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico Ativo , Proteínas de Transporte/metabolismo , Complexo de Golgi/metabolismo , Humanos , Ligantes , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Modelos Biológicos , Modelos Moleculares , Oxisteróis/metabolismo , Domínios e Motivos de Interação entre Proteínas , Receptores de Esteroides/química , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Replicação Viral/fisiologia
5.
Immunity ; 54(7): 1433-1446.e5, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34062116

RESUMO

The extra-embryonic yolk sac contains the first definitive multipotent hematopoietic cells, denominated erythromyeloid progenitors. They originate in situ prior to the emergence of hematopoietic stem cells and give rise to erythroid, monocytes, granulocytes, mast cells and macrophages, the latter in a Myb transcription factor-independent manner. We uncovered here the heterogeneity of yolk sac erythromyeloid progenitors, at the single cell level, and discriminated multipotent from committed progenitors, prior to fetal liver colonization. We identified two temporally distinct megakaryocyte differentiation pathways. The first occurs in the yolk sac, bypasses intermediate bipotent megakaryocyte-erythroid progenitors and, similar to the differentiation of macrophages, is Myb-independent. By contrast, the second originates later, from Myb-dependent bipotent progenitors expressing Csf2rb and colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes. Understanding megakaryocyte development is crucial as they play key functions during vascular development, in particular in separating blood and lymphatic networks.


Assuntos
Diferenciação Celular/fisiologia , Eritrócitos/citologia , Megacariócitos/citologia , Células Mieloides/citologia , Células-Tronco/citologia , Saco Vitelino/citologia , Animais , Linhagem da Célula/fisiologia , Células Cultivadas , Embrião de Mamíferos/citologia , Feminino , Granulócitos/citologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Células-Tronco Multipotentes/citologia , Gravidez
6.
EMBO J ; 43(5): 666-694, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38279026

RESUMO

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase , Neoplasias , Humanos , Ciclossomo-Complexo Promotor de Anáfase/genética , Dineínas , Cinesinas/genética , Cinetocoros , Mitose , Neoplasias/genética
7.
Mol Cell ; 77(3): 618-632.e5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806350

RESUMO

TMEM39A, encoding an ER-localized transmembrane protein, is a susceptibility locus for multiple autoimmune diseases. The molecular function of TMEM39A remains completely unknown. Here we demonstrated that TMEM39A, also called SUSR2, modulates autophagy activity by regulating the spatial distribution and levels of PtdIns(4)P. Depletion of SUSR2 elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote assembly of the SNARE complex for autophagosome maturation. SUSR2 knockdown also increases the degradative capability of lysosomes. Mechanistically, SUSR2 interacts with the ER-localized PtdIns(4)P phosphatase SAC1 and also the COPII SEC23/SEC24 subunits to promote the ER-to-Golgi transport of SAC1. Retention of SAC1 on the ER in SUSR2 knockdown cells increases the level of PtdIns(3)P produced by the VPS34 complex, promoting autophagosome formation. Our study reveals that TMEM39A/SUSR2 acts as an adaptor protein for efficient export of SAC1 from the ER and provides insights into the pathogenesis of diseases associated with TMEM39A mutations.


Assuntos
Autofagia/fisiologia , Proteínas de Membrana/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células COS , Chlorocebus aethiops , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Células HEK293 , Células HeLa , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/fisiologia , Fosfatos de Fosfatidilinositol/metabolismo , Fosfatidilinositóis/metabolismo , Monoéster Fosfórico Hidrolases/fisiologia , Transporte Proteico/fisiologia
8.
Development ; 151(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38546043

RESUMO

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.


Assuntos
Pontos de Checagem da Fase M do Ciclo Celular , Meiose , Animais , Feminino , Camundongos , Ciclossomo-Complexo Promotor de Anáfase/genética , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Oócitos/metabolismo , Ubiquitinas/metabolismo
9.
Immunity ; 48(6): 1160-1171.e5, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29858009

RESUMO

Hematopoiesis occurs in distinct waves. "Definitive" hematopoietic stem cells (HSCs) with the potential for all blood lineages emerge in the aorta-gonado-mesonephros, while "primitive" progenitors, whose potential is thought to be limited to erythrocytes, megakaryocytes, and macrophages, arise earlier in the yolk sac (YS). Here, we questioned whether other YS lineages exist that have not been identified, partially owing to limitations of current lineage tracing models. We established the use of Cdh5-CreERT2 for hematopoietic fate mapping, which revealed the YS origin of mast cells (MCs). YS-derived MCs were replaced by definitive MCs, which maintained themselves independently from the bone marrow in the adult. Replacement occurred with tissue-specific kinetics. MCs in the embryonic skin, but not other organs, remained largely YS derived prenatally and were phenotypically and transcriptomically distinct from definite adult MCs. We conclude that within myeloid lineages, dual hematopoietic origin is shared between macrophages and MCs.


Assuntos
Linhagem da Célula/imunologia , Hematopoese/fisiologia , Mastócitos/citologia , Animais , Hemangioblastos/citologia , Células-Tronco Hematopoéticas/citologia , Macrófagos/citologia , Macrófagos/imunologia , Mastócitos/imunologia , Camundongos , Pele/citologia , Pele/imunologia , Saco Vitelino/citologia , Saco Vitelino/embriologia
10.
Immunity ; 49(4): 640-653.e5, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332630

RESUMO

Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.


Assuntos
Células Eritroides/imunologia , Mastócitos/imunologia , Células Progenitoras Mieloides/imunologia , Animais , Linhagem da Célula/imunologia , Células Cultivadas , Tecido Conjuntivo/imunologia , Tecido Conjuntivo/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/imunologia , Células Eritroides/citologia , Células Eritroides/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Cadeias beta de Integrinas/imunologia , Cadeias beta de Integrinas/metabolismo , Mastócitos/citologia , Mastócitos/metabolismo , Camundongos Transgênicos , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/metabolismo
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