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1.
Cell ; 184(14): 3702-3716.e30, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34133940

RESUMO

Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required ß1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.


Assuntos
Junções Célula-Matriz/metabolismo , Morfogênese , Animais , Membrana Basal/metabolismo , Adesão Celular , Divisão Celular , Movimento Celular , Rastreamento de Células , Embrião de Mamíferos/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Integrinas/metabolismo , Camundongos , Modelos Biológicos , Glândulas Salivares/citologia , Glândulas Salivares/embriologia , Glândulas Salivares/metabolismo , Transcriptoma/genética
2.
Cell ; 180(2): 233-247.e21, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978343

RESUMO

Wnt dependency and Lgr5 expression define multiple mammalian epithelial stem cell types. Under defined growth factor conditions, such adult stem cells (ASCs) grow as 3D organoids that recapitulate essential features of the pertinent epithelium. Here, we establish long-term expanding venom gland organoids from several snake species. The newly assembled transcriptome of the Cape coral snake reveals that organoids express high levels of toxin transcripts. Single-cell RNA sequencing of both organoids and primary tissue identifies distinct venom-expressing cell types as well as proliferative cells expressing homologs of known mammalian stem cell markers. A hard-wired regional heterogeneity in the expression of individual venom components is maintained in organoid cultures. Harvested venom peptides reflect crude venom composition and display biological activity. This study extends organoid technology to reptilian tissues and describes an experimentally tractable model system representing the snake venom gland.


Assuntos
Técnicas de Cultura de Células/métodos , Organoides/crescimento & desenvolvimento , Venenos de Serpentes/metabolismo , Células-Tronco Adultas/metabolismo , Animais , Cobras Corais/metabolismo , Perfilação da Expressão Gênica/métodos , Organoides/metabolismo , Glândulas Salivares/metabolismo , Venenos de Serpentes/genética , Serpentes/genética , Serpentes/crescimento & desenvolvimento , Células-Tronco/metabolismo , Toxinas Biológicas/genética , Transcriptoma/genética
3.
Cell ; 171(1): 242-255.e27, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28938116

RESUMO

The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology, and spatial patterning, are encoded. Here, we show that, in mouse mammary gland, kidney, and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures develop as a self-organized process, reliant upon a strikingly simple but generic rule, without recourse to a rigid and deterministic sequence of genetically programmed events.


Assuntos
Rim/crescimento & desenvolvimento , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Modelos Biológicos , Morfogênese , Próstata/crescimento & desenvolvimento , Animais , Feminino , Humanos , Rim/embriologia , Masculino , Glândulas Mamárias Humanas/embriologia , Camundongos , Próstata/embriologia
4.
Genes Dev ; 38(11-12): 569-582, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38997156

RESUMO

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.


Assuntos
Homeostase , Regeneração , Telomerase , Telomerase/metabolismo , Telomerase/genética , Animais , Homeostase/genética , Homeostase/efeitos da radiação , Camundongos , Regeneração/efeitos da radiação , Regeneração/genética , Humanos , Glândulas Salivares/efeitos da radiação , Glândulas Salivares/metabolismo , Glândulas Salivares/citologia , Proliferação de Células/efeitos da radiação , Proliferação de Células/genética , Sobrevivência Celular/efeitos da radiação , Sobrevivência Celular/genética , Glândula Submandibular/efeitos da radiação , Glândula Submandibular/metabolismo , Células-Tronco/efeitos da radiação , Células-Tronco/metabolismo , Células-Tronco/citologia , Radioterapia/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas
5.
CA Cancer J Clin ; 73(6): 597-619, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37490348

RESUMO

Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.


Assuntos
Neoplasias das Glândulas Salivares , Humanos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/terapia
6.
Physiol Rev ; 102(3): 1495-1552, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35343828

RESUMO

Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.


Assuntos
Regeneração , Glândulas Salivares , Linhagem da Célula , Humanos , Saúde Bucal , Regeneração/fisiologia , Glândulas Salivares/fisiologia , Transdução de Sinais
7.
Genes Dev ; 34(3-4): 179-193, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31879358

RESUMO

The GATA-type zinc finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, while being essential for growth and differentiation of normal mammary epithelial cells.


Assuntos
Neoplasias da Mama/fisiopatologia , Carcinogênese/genética , Diferenciação Celular/genética , Células Epiteliais/citologia , Proteínas Repressoras/metabolismo , Animais , Neoplasias da Mama/genética , Caderinas/genética , Sobrevivência Celular/genética , Cromatina/genética , Cromatina/metabolismo , Modelos Animais de Doenças , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos , Ligação Proteica/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética
8.
Physiol Rev ; 100(2): 489-523, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539305

RESUMO

The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.


Assuntos
Diferenciação Celular , Linhagem da Célula , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Humanas/patologia , Morfogênese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Transdução de Sinais , Células-Tronco/patologia , Fatores de Transcrição/genética , Microambiente Tumoral
9.
Development ; 151(15)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39092607

RESUMO

Branching morphogenesis is a characteristic feature of many essential organs, such as the lung and kidney, and most glands, and is the net result of two tissue behaviors: branch point initiation and elongation. Each branched organ has a distinct architecture customized to its physiological function, but how patterning occurs in these ramified tubular structures is a fundamental problem of development. Here, we use quantitative 3D morphometrics, time-lapse imaging, manipulation of ex vivo cultured mouse embryonic organs and mice deficient in the planar cell polarity component Vangl2 to address this question in the developing mammary gland. Our results show that the embryonic epithelial trees are highly complex in topology owing to the flexible use of two distinct modes of branch point initiation: lateral branching and tip bifurcation. This non-stereotypy was contrasted by the remarkably constant average branch frequency, indicating a ductal growth invariant, yet stochastic, propensity to branch. The probability of branching was malleable and could be tuned by manipulating the Fgf10 and Tgfß1 pathways. Finally, our in vivo data and ex vivo time-lapse imaging suggest the involvement of tissue rearrangements in mammary branch elongation.


Assuntos
Glândulas Mamárias Animais , Morfogênese , Animais , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Feminino , Fator 10 de Crescimento de Fibroblastos/metabolismo , Fator 10 de Crescimento de Fibroblastos/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Fator de Crescimento Transformador beta1/metabolismo , Imagem com Lapso de Tempo , Polaridade Celular , Embrião de Mamíferos/metabolismo , Transdução de Sinais
10.
Development ; 151(16)2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39087588

RESUMO

The Spalt transcriptional regulators participate in a variety of cell fate specification processes during development, regulating transcription through interactions with DNA AT-rich regions. Spalt proteins also bind to heterochromatic regions, and some of their effects require interactions with the NuRD chromatin remodeling and deacetylase complex. Most of the biological roles of Spalt proteins have been characterized in diploid cells engaged in cell proliferation. Here, we address the function of Drosophila Spalt genes in the development of a larval tissue formed by polyploid cells, the prothoracic gland, the cells of which undergo several rounds of DNA replication without mitosis during larval development. We show that prothoracic glands depleted of Spalt expression display severe changes in the size of the nucleolus, the morphology of the nuclear envelope and the disposition of the chromatin within the nucleus, leading to a failure in the synthesis of ecdysone. We propose that loss of ecdysone production in the prothoracic gland of Spalt mutants is primarily caused by defects in nuclear pore complex function that occur as a consequence of faulty interactions between heterochromatic regions and the nuclear envelope.


Assuntos
Proteínas de Drosophila , Ecdisona , Fatores de Transcrição , Animais , Nucléolo Celular/metabolismo , Cromatina/metabolismo , Drosophila/metabolismo , Drosophila/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Ecdisona/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Larva/metabolismo , Larva/crescimento & desenvolvimento , Larva/genética , Mutação/genética , Membrana Nuclear/metabolismo , Membrana Nuclear/genética , Poro Nuclear/metabolismo , Poro Nuclear/genética , Proteínas Repressoras , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
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