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1.
Front Immunol ; 12: 719979, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34381461

RESUMEN

Adipose tissue macrophages (ATMs) regulate homeostasis and contribute to the metabolically harmful chronic inflammation in obese individuals. While evident heterogeneity of resident ATMs has been described previously, their phenotype, developmental origin, and functionality remain inconsistent. We analyzed white adipose tissue (WAT) during homeostasis and diet interventions using comprehensive and unbiased single-cell mass cytometry and genetic lineage tracking models. We now provide a uniform definition of individual subsets of resident ATMs. We show that in lean mice, WAT co-harbors eight kinetically evolving CD206+ macrophage subpopulations (defined by TIM4, CD163, and MHC II) and two CD206- macrophage subpopulations. TIM4-CD163+, TIM4-CD163- and CD206- macrophage populations are largely bone marrow-derived, while the proliferating TIM4+CD163+ subpopulation is of embryonic origin. All macrophage subtypes are active in phagocytosis, endocytosis, and antigen processing in vitro, whereas TIM4+CD163+ cells are superior in scavenging in vivo. A high-fat diet induces massive infiltration of CD206- macrophages and selective down-regulation of MHC II on TIM4+ macrophages. These changes are reversed by dietary intervention. Thus, the developmental origin and environment jointly regulate the functional malleability of resident ATMs.


Asunto(s)
Tejido Adiposo Blanco/metabolismo , Macrófagos/metabolismo , Proteoma/metabolismo , Proteómica , Análisis de la Célula Individual , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/inmunología , Animales , Biomarcadores , Diferenciación Celular , Plasticidad de la Célula/genética , Plasticidad de la Célula/inmunología , Reprogramación Celular , Biología Computacional , Metabolismo Energético , Inmunohistoquímica , Inmunofenotipificación , Macrófagos/inmunología , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Fagocitosis , Proteómica/métodos , Análisis de la Célula Individual/métodos
2.
Eur J Immunol ; 50(10): 1500-1514, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32459864

RESUMEN

Macrophages, which are highly diverse in different tissues, play a complex and vital role in tissue development, homeostasis, and inflammation. The origin and heterogeneity of tissue-resident monocytes and macrophages in ovaries remains unknown. Here we identify three tissue-resident monocyte populations and five macrophage populations in the adult ovaries using high-dimensional single cell mass cytometry. Ontogenic analyses using cell fate mapping models and cell depletion experiments revealed the infiltration of ovaries by both yolk sac and fetal liver-derived macrophages already during the embryonic development. Moreover, we found that both embryonic and bone marrow-derived macrophages contribute to the distinct ovarian macrophage subpopulations in the adults. These assays also showed that fetal-derived MHC II-negative macrophages differentiate postnatally in the maturing ovary to MHC II-positive cells. Our analyses further unraveled that the developmentally distinct macrophage types share overlapping distribution and scavenging function in the ovaries under homeostatic conditions. In conclusion, we report here the first comprehensive analyses of ovarian monocytes and macrophages. In addition, we show that the mechanisms controlling monocyte immigration, the phenotype of different pools of interstitial macrophages, and the interconversion capacity of fetal-derived macrophages in ovaries are remarkably different from those seen in other tissue niches.


Asunto(s)
Macrófagos/fisiología , Monocitos/fisiología , Ovario/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Femenino , Feto , Homeostasis , Inflamación , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de la Célula Individual
3.
FASEB J ; 32(6): 3229-3241, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29401623

RESUMEN

The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17ß) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17ß-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.-Hakkarainen, J., Zhang, F.-P., Jokela, H., Mayerhofer, A., Behr, R., Cisneros-Montalvo, S., Nurmio, M., Toppari, J., Ohlsson, C., Kotaja, N., Sipilä, P., Poutanen, M. Hydroxysteroid (17ß) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/biosíntesis , Fertilidad/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Células de Sertoli/enzimología , Espermatogénesis/fisiología , Esteroides/biosíntesis , 17-Hidroxiesteroide Deshidrogenasas/genética , Animales , Masculino , Ratones , Ratones Noqueados , Epitelio Seminífero/citología , Epitelio Seminífero/enzimología , Células de Sertoli/citología , Espermátides/citología , Espermátides/enzimología
4.
Sci Rep ; 7(1): 16406, 2017 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-29180785

RESUMEN

HSD17B1 is a steroid metabolising enzyme. We have previously generated knockout mice that had the entire coding region of Hsd17b1 replaced with lacZ-neo cassette (Hsd17b1-LacZ/Neo mice). This resulted in a 90% reduction of HSD17B1 activity, associated with severe subfertility in the knockout females. The present study indicates that Hsd17b1-LacZ/Neo male mice have a metabolic phenotype, including reduced adipose mass, increased lean mass and lipid accumulation in the liver. During the characterisation of this metabolic phenotype, it became evident that the expression of the Naglu gene, located closely upstream of Hsd17b1, was severely reduced in all tissues analysed. Similar results were obtained from Hsd17b1-LacZ mice after removing the neo cassette from the locus or by crossing the Hsd17b1-LacZ/Neo mice with transgenic mice constitutively expressing human HSD17B1. The deficiency of Naglu caused the accumulation of glycosaminoglycans in all studied mouse models lacking the Hsd17b1 gene. The metabolic phenotypes of the Hsd17b1 knockout mouse models were recapitulated in Naglu knockout mice. Based on the data we propose that the Hsd17b1 gene includes a regulatory element controlling Naglu expression and the metabolic phenotype in mice lacking the Hsd17b1 genomic region is caused by the reduced expression of Naglu rather than the lack of Hsd17b1.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Alelos , Eliminación de Gen , Estudios de Asociación Genética , Enfermedades por Almacenamiento Lisosomal/genética , Fenotipo , Animales , Modelos Animales de Enfermedad , Expresión Génica , Sitios Genéticos , Glicosaminoglicanos/metabolismo , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/metabolismo , Lisosomas/metabolismo , Masculino , Ratones , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/genética , Mucopolisacaridosis III/metabolismo
5.
FASEB J ; 29(9): 3806-16, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26018678

RESUMEN

Hydroxysteroid (17ß)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testosterone (T) and E2, respectively. In this study, the importance of HSD17B1 in ovarian estrogen production was determined using Hsd17b1 knockout (HSD17B1KO) mice. In these mice, the ovarian HSD17B enzyme activity was markedly reduced, indicating a central role of HSD17B1 in ovarian physiology. The lack of Hsd17b activity resulted in increased ovarian E1:E2 and A-dione:T ratios, but we also observed reduced progesterone concentration in HSD17B1KO ovaries. Accordingly with the altered steroid production, altered expression of Star, Cyp11a1, Lhcgr, Hsd17b7, and especially Cyp17a1 was observed. The ovaries of HSD17B1KO mice presented with all stages of folliculogenesis, while the corpus luteum structure was less defined and number reduced. Surprisingly, bundles of large granular cells of unknown origin appeared in the stroma of the KO ovaries. The HSD17B1KO mice presented with severe subfertility and failed to initiate pseudopregnancy. However, the HSD17B1KO females presented with normal estrous cycle defined by vaginal smears and normal puberty appearance. This study indicates that HSD17B1 is a key enzyme in ovarian steroidogenesis and has a novel function in initiation and stabilization of pregnancy.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Ciclo Estral , Infertilidad Femenina/enzimología , Luteinización , Ovario/metabolismo , Progesterona/biosíntesis , 17-Hidroxiesteroide Deshidrogenasas/biosíntesis , 17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/biosíntesis , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Femenino , Infertilidad Femenina/genética , Masculino , Ratones , Ratones Noqueados , Ovario/patología , Fosfoproteínas/biosíntesis , Fosfoproteínas/genética , Embarazo , Progesterona/genética , Maduración Sexual/genética , Esteroide 17-alfa-Hidroxilasa/biosíntesis , Esteroide 17-alfa-Hidroxilasa/genética
6.
J Endocrinol ; 212(1): 27-40, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22045753

RESUMEN

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17ß) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17ß-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studies in vitro and in vivo are to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Animales , Redes y Vías Metabólicas , Ratones , Ratones Transgénicos , Modelos Animales , Fenotipo
7.
Hum Mol Genet ; 19(15): 3021-9, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20484223

RESUMEN

Mutations of the PALB2 tumor suppressor gene in humans are associated with hereditary predisposition to breast and also some other cancers. In the present study, we have characterized mice deficient in Palb2. The data show that the Palb2((+/-)) mice are normal and fertile, and lack macroscopic tumors when followed up till the age of 8 months. Homozygous (HO) Palb2((-/-)) mice present with embryonic lethality and die at E9.5 at the latest. The mutant embryos are smaller in size, developmentally retarded and display defective mesoderm differentiation after gastrulation. In Palb2((-/-)) embryos, the expression of cyclin-dependent kinase inhibitor p21 is increased, and Palb2((-/-)) blastocysts show a growth defect in vitro. Hence, the phenotype of the Palb2((-/-)) mice in many regards resembles those previously reported for Brca1 and Brca2 knockout mice. The similarity in the phenotypes between Palb2, Brca1 and Brca2 knockout mice further supports the functional relationship shown in vitro for these three proteins. Accordingly, our data in vivo suggest that a key function for PALB2 is to interact with and to build up appropriate communication between BRCA1 and BRCA2, thereby licensing the successful performance of the physiological tasks mediated by these two proteins, particularly in homologous recombination and in proper DNA damage response signaling.


Asunto(s)
Diferenciación Celular/genética , Pérdida del Embrión/genética , Desarrollo Embrionario , Silenciador del Gen , Mesodermo/patología , Proteínas Supresoras de Tumor/genética , Animales , Biomarcadores/metabolismo , Blastocisto/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Pérdida del Embrión/patología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Regulación del Desarrollo de la Expresión Génica , Heterocigoto , Mesodermo/metabolismo , Ratones , Mutación/genética , Proteínas Supresoras de Tumor/metabolismo
8.
Endocrinology ; 151(4): 1884-92, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20185768

RESUMEN

Hydroxysteroid (17beta) dehydrogenase 7 (HSD17B7) has been shown to catalyze the conversion of both estrone to estradiol (17-ketosteroid reductase activity) and zymosterone to zymosterol (3-ketosteroid reductase activity involved in cholesterol biosynthesis) in vitro. To define the metabolic role of the enzyme in vivo, we generated knockout mice deficient in the enzyme activity (HSD17B7KO). The data showed that the lack of HSD17B7 results in a blockage in the de novo cholesterol biosynthesis in mouse embryos in vivo, and HSD17BKO embryos die at embryonic day (E) 10.5. Analysis of neural structures revealed a defect in the development of hemispheres of the front brain with an increased apoptosis in the neuronal tissues. Morphological defects in the cardiovascular system were also observed from E9.5 onward. Mesodermal, endodermal, and hematopoietic cells were all detected by the histological analysis of the visceral yolk sac, whereas no organized vessels were observed in the knockout yolk sac. Immunohistological staining for platelet endothelial cell adhesion molecule-1 indicated that the complexity of the vasculature also was reduced in the HSD17B7KO embryos, particularly in the head capillary plexus and branchial arches. At E8.5-9.5, the heart development and the looping of the heart appeared to be normal in the HSD17B7KO embryos. However, at E10.5 the heart was dilated, and the thickness of the cardiac muscle and pericardium in the HSD17B7KO embryos was markedly reduced, and immunohistochemical staining for GATA-4 revealed that HSD17B7KO embryos had a reduced number of myocardial cells. The septum of the atrium was also defected in the knockout mice.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Diferenciación Celular/genética , Colesterol/biosíntesis , Corazón/embriología , Placa Neural/embriología , 17-Hidroxiesteroide Deshidrogenasas/genética , Animales , Apoptosis/genética , Vasos Sanguíneos/embriología , Vasos Sanguíneos/enzimología , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Ratones , Ratones Noqueados , Miocardio/enzimología , Placa Neural/enzimología , Saco Vitelino/irrigación sanguínea , Saco Vitelino/embriología
9.
Am J Pathol ; 176(3): 1443-51, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20093485

RESUMEN

Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction, which triggers a rise in circulating progesterone levels, and in response to exogenous progestins. Strikingly, a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment, although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/patología , Inhibidores Enzimáticos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Hiperplasia Endometrial/enzimología , Inhibidores Enzimáticos/farmacología , Estradiol/metabolismo , Estrógenos , Femenino , Humanos , Ratones , Ratones Transgénicos , Tamaño de los Órganos/efectos de los fármacos , Progestinas/uso terapéutico , Útero/efectos de los fármacos , Útero/enzimología , Útero/crecimiento & desarrollo , Útero/patología
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