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1.
J Immunol ; 202(3): 956-965, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30617224

RESUMEN

The cytokine IL-22 is rapidly induced at barrier surfaces where it regulates host-protective antimicrobial immunity and tissue repair but can also enhance disease severity in some chronic inflammatory settings. Using the chronic Salmonella gastroenteritis model, Ab-mediated neutralization of IL-22 impaired intestinal epithelial barrier integrity and, consequently, exaggerated expression of proinflammatory cytokines. As disease normally resolved, neutralization of IL-22 caused luminal narrowing of the cecum-a feature reminiscent of fibrotic strictures seen in Crohn disease patients. Corresponding to the exaggerated immunopathology caused by IL-22 suppression, Salmonella burdens in the gut were reduced. This enhanced inflammation and pathogen clearance was associated with alterations in gut microbiome composition, including the overgrowth of Bacteroides acidifaciens Our findings thus indicate that IL-22 plays a protective role by limiting infection-induced gut immunopathology but can also lead to persistent pathogen colonization.


Asunto(s)
Gastroenteritis/inmunología , Microbioma Gastrointestinal , Interleucinas/inmunología , Salmonelosis Animal/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Anticuerpos Neutralizantes/inmunología , Bacteroides , Ciego/inmunología , Ciego/patología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Citocinas/inmunología , Gastroenteritis/microbiología , Inflamación , Interleucinas/antagonistas & inhibidores , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Inducción de Remisión , Salmonelosis Animal/terapia , Salmonella typhimurium , Interleucina-22
2.
Clin Sci (Lond) ; 133(3): 443-447, 2019 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-30737302

RESUMEN

In the last two decades, our understanding of the genetic underpinnings of inherited podocytopathies has advanced immensely. By sequencing the genomes of a large pool of families affected by focal segmental glomerulosclerosis (FSGS), researchers have identified a common theme: familial podocytopathies are frequently caused by genes selectively expressed in podocytes. Podocalyxin is a podocyte-specific surface sialomucin that has long been known to play important roles in podocyte morphogenesis and function. Few studies, however, have shown a conclusive link between mutations in the gene and FSGS complemented by functional evidence. In a fascinating new paper published in Clinical Science, Lin et al. identify two unrelated pedigrees in which dominant loss-of-function mutations in PODXL lead to adult-onset FSGS. Nonsense-mediated decay of the mutated PODXL transcripts leads to protein insufficiency, which in turn cause podocyte dysfunction through defects in motility and cytoskeletal organization. This is the first study to date that demonstrates, mechanistically, how autosomal dominant mutations in podocalyxin can lead to FSGS and renal insufficiency. Here, we summarize the experimental findings of this manuscript and propose, perhaps, a more controversial hypothesis: down-regulation of podocalyxin protein expression from podocytes is a critical turning point in the progression of most podocytopathies and may be mechanistically relevant to glomerulopathies in which podocyte damage is not necessarily induced by genetic lesions.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Podocitos , Adulto , Codón sin Sentido , Humanos , Sialoglicoproteínas
3.
Stem Cells ; 35(12): 2366-2378, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28905451

RESUMEN

A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. Podocytes derived from human pluripotent stem cells (hPSC-podocytes) have recently been generated in nephron-like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC-podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC-podocytes in vitro progressively establish junction-rich basal membranes (nephrin+ podocin+ ZO-1+ ) and microvillus-rich apical membranes (podocalyxin+ ), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin-knockout hPSCs and derived podocytes, generated using CRISPR/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin-deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC-podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration. Stem Cells 2017;35:2366-2378.


Asunto(s)
Organoides/metabolismo , Podocitos/metabolismo , Animales , Adhesión Celular/genética , Adhesión Celular/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Edición Génica , Humanos , Riñón/metabolismo , Riñón/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Ratones , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo
4.
Exp Hematol ; 86: 1-14, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32422232

RESUMEN

The CD34 cell surface antigen is widely expressed in tissues on cells with progenitor-like properties and on mature vascular endothelia. In adult human bone marrow, CD34 marks hematopoietic stem and progenitor cells (HSPCs) starting from the bulk of hematopoietic stem cells with long-term repopulating potential (LT-HSCs) throughout expansion and differentiation of oligopotent and unipotent progenitors. CD34 protein surface expression is typically lost as cells mature into terminal effectors. Because of this expression pattern of HSPCs, CD34 has had a central role in the evaluation or selection of donor graft tissue in HSC transplant (HSCT). Given its clinical importance, it is surprising that the biological functions of CD34 are still poorly understood. This enigma is due, in part, to CD34's context-specific role as both a pro-adhesive and anti-adhesive molecule and its potential functional redundancy with other sialomucins. Moreover, there are also critical differences in the regulation of CD34 expression on HSPCs in humans and experimental mice. In this review, we highlight some of the more well-defined functions of CD34 in HSPCs with a focus on proposed functions most relevant to HSCT biology.


Asunto(s)
Antígenos CD34/metabolismo , Diferenciación Celular , Células Madre Hematopoyéticas/metabolismo , Animales , Médula Ósea/metabolismo , Regulación de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Humanos , Ratones
5.
Sci Rep ; 10(1): 9419, 2020 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-32523052

RESUMEN

Dominant and recessive mutations in podocalyxin (PODXL) are associated with human kidney disease. Interestingly, some PODXL mutations manifest as anuria while others are associated with proteinuric kidney disease. PODXL heterozygosity is associated with adult-onset kidney disease and podocalyxin shedding into the urine is a common biomarker of a variety nephrotic syndromes. It is unknown, however, how various lesions in PODXL contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes Podxl in developmentally mature podocytes (Podxl∆Pod) and a second that is heterozygous for podocalyxin in all tissues (Podxl+/-). We used histologic and ultrastructural analyses, as well as clinical chemistry assays to evaluate kidney development and function in these strains. In contrast to null knockout mice (Podxl-/-), which die shortly after birth from anuria and hypertension, Podxl∆Pod mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. Podxl+/- mice, in contrast, have a normal lifespan, and fail to develop kidney disease under normal conditions. Intriguingly, although wild-type C57Bl/6 mice are resistant to puromycin aminonucleoside (PA)-induced nephrosis (PAN), Podxl+/- mice are highly sensitive and PA induces severe proteinuria and collapsing FSGS. In summary, we find that the developmental timepoint at which podocalyxin is ablated (immature vs. mature podocytes) has a profound effect on the urinary phenotype due to its critical roles in both the formation and the maintenance of podocyte ultrastructure. In addition, Podxl∆Pod and Podxl+/- mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.


Asunto(s)
Enfermedades Renales/metabolismo , Podocitos/metabolismo , Sialoglicoproteínas/metabolismo , Animales , Femenino , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Heterocigoto , Humanos , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Fenotipo , Podocitos/patología , Proteinuria/metabolismo , Proteinuria/patología , Puromicina Aminonucleósido/metabolismo
6.
Dev Cell ; 37(1): 47-57, 2016 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-27046831

RESUMEN

Intestinal tumorigenesis is a result of mutations in signaling pathways that control cellular proliferation, differentiation, and survival. Mutations in the Wnt/ß-catenin pathway are associated with the majority of intestinal cancers, while dysregulation of the Hippo/Yes-Associated Protein (YAP) pathway is an emerging regulator of intestinal tumorigenesis. In addition, these closely related pathways play a central role during intestinal regeneration. We have previously shown that methylation of the Hippo transducer YAP by the lysine methyltransferase SETD7 controls its subcellular localization and function. We now show that SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration. Mechanistically, SETD7 is part of a complex containing YAP, AXIN1, and ß-catenin, and SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of ß-catenin. Collectively, these results define a methyltransferase-dependent regulatory mechanism that links the Wnt/ß-catenin and Hippo/YAP pathways during intestinal regeneration and tumorigenesis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias Intestinales/patología , Fosfoproteínas/metabolismo , Proteína Metiltransferasas/metabolismo , Proteínas Wnt/genética , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteína Axina/genética , Células CACO-2 , Proteínas de Ciclo Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Células HEK293 , N-Metiltransferasa de Histona-Lisina , Humanos , Neoplasias Intestinales/genética , Intestinos/patología , Células MCF-7 , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas/genética , Proteína Metiltransferasas/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , Vía de Señalización Wnt/fisiología , Proteínas Señalizadoras YAP , beta Catenina/genética
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