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1.
Nature ; 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-38057666

RESUMEN

Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.

2.
Biochem Biophys Res Commun ; 669: 113-119, 2023 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-37269593

RESUMEN

BACKGROUND: Muscle aging is associated with muscle stem cell (MuSC) senescence, a process of whose DNA damage accumulation is considered as one of the leading causes. BTG2 had been identified as a mediator of genotoxic and cellular stress signaling pathways, however, its role in senescence of stem cells, including MuSC, remains unknown. METHOD: We first compared MuSCs isolated from young and old mice to evaluate our in vitro model of natural senescence. CCK8 and EdU assays were utilized to assess the proliferation capacity of the MuSCs. Cellular senescence was further assessed at biochemical levels by SA-ß-Gal and γHA2.X staining, and at molecular levels by quantifying the expression of senescence-associated genes. Next, by performing genetic analysis, we identified Btg2 as a potential regulator of MuSC senescence, which was experimentally validated by Btg2 overexpression and knockdown in primary MuSCs. Lastly, we extended our research to humans by analyzing the potential links between BTG2 and muscle function decline in aging. RESULTS: BTG2 is highly expressed in MuSCs from elder mice showing senescent phenotypes. Overexpression and knockdown of Btg2 stimulates and prevents MuSCs senescence, respectively. In humans, high level of BTG2 is associated with low muscle mass in aging, and is a risk factor of aging-related diseases, such as diabetic retinopathy and HDL cholesterol. CONCLUSION: Our work demonstrates BTG2 as a regulator of MuSC senescence and may serve as an intervention target for muscle aging.


Asunto(s)
Proteínas Inmediatas-Precoces , Enfermedades Musculares , Animales , Humanos , Ratones , Envejecimiento/fisiología , Senescencia Celular , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Músculo Esquelético/fisiología , Músculos , Enfermedades Musculares/metabolismo , Células Madre/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
3.
Cell Prolif ; 54(2): e12968, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33332660

RESUMEN

OBJECTIVES: Pre-eclampsia is a leading cause of morbidity and mortality during pregnancy. Although the two forms of this disorder, early- (EOPE) and late-onset of pre-eclampsia (LOPE) are different, the underlying pathology remains elusive. We aim to unravel the difference and to identify novel biomarkers for EOPE and LOPE. MATERIALS AND METHODS: A complete comparison of both placental and peripheral blood transcriptomes was performed to investigate the pathology of pre-eclampsia. Single-cell transcriptomics of the maternal-fetal interface were integrated to identify novel biomarkers for EOPE and LOPE which were further verified at protein or mRNA level in patients. RESULTS: We found that the transcriptomes of placentae from EOPE, but not LOPE, were significantly different from their respective controls. Conversely, the transcriptomes of peripheral blood from LOPE were more different from their controls than EOPE. Importantly, we identified that several classical biomarkers of pre-eclampsia were expressed specifically in extravillous trophoblast and syncytiotrophoblast and only upregulated in EOPE, suggesting they should not be applied to all pre-eclampsia patients in general. We further identified novel biomarkers for EOPE and LOPE from differentially expressed genes (DEGs) of placental and peripheral blood, respectively. The new biomarkers EBI3, IGF2, ORMDL3, GATA2 and KIR2DL4 were experimentally verified with patient blood samples. CONCLUSION: Our data demonstrate distinct pathology of EOPE and LOPE, and uncover new biomarkers that can be applied in diagnosis for pre-eclampsia.


Asunto(s)
Biomarcadores/metabolismo , Preeclampsia/patología , Transcriptoma , Biomarcadores/sangre , Estudios de Casos y Controles , Biología Computacional , Femenino , Factor de Transcripción GATA2/sangre , Factor de Transcripción GATA2/metabolismo , Humanos , Interleucinas/sangre , Interleucinas/metabolismo , Enfermedades de Inicio Tardío , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Antígenos de Histocompatibilidad Menor/sangre , Antígenos de Histocompatibilidad Menor/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Embarazo , Mapas de Interacción de Proteínas , ARN Mensajero/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual
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