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1.
Cell ; 178(1): 242-260.e29, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31155234

RESUMO

Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.


Assuntos
Miocárdio/metabolismo , Biossíntese de Proteínas , Adolescente , Adulto , Idoso , Animais , Códon/genética , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ribossomos/genética , Ribossomos/metabolismo , Adulto Jovem
2.
Cancer Immunol Immunother ; 69(7): 1307-1313, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32193699

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare aggressive sarcomas with poor prognosis. More than half of MPNSTs develop from benign precursor tumors associated with neurofibromatosis type 1 (NF1) which is a tumor suppressor gene disorder. Early detection of malignant transformation in NF1 patients is pivotal to improving survival. The primary aim of this study was to evaluate the role of immuno-modulators as candidate biomarkers of malignant transformation in NF1 patients with plexiform neurofibromas as well as predictors of response to immunotherapeutic approaches. METHODS: Sera from a total of 125 NF1 patients with quantified internal tumor load were included, and 25 of them had MPNSTs. A total of six immuno-modulatory factors (IGFBP-1, PD-L1, IFN-α, GM-CSF, PGE-2, and AXL) were measured in these sera using respective ELISA. RESULTS: NF1 patients with MPNSTs had significantly elevated PD-L1 levels in their sera compared to NF1 patients without MPNSTs. By contrast, AXL concentrations were significantly lower in sera of NF1-MPNST patients. IGFBP-1 and PGE2 serum levels did not differ between the two patient groups. IFN-α and GM-CSF were below the detectable level in most samples. CONCLUSION: The immuno-modulator PD-L1 is upregulated in MPNST patients and therefore may provide as a potential biomarker of malignant transformation in patients with NF1 and as a response predictor for immunotherapeutic approaches.


Assuntos
Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Neurofibrossarcoma/sangue , Neurofibrossarcoma/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Prognóstico , Carga Tumoral
3.
Cell Mol Life Sci ; 76(1): 179-192, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30310934

RESUMO

Human pluripotent stem cells (hPSCs) provide a source for the generation of defined kidney cells and renal organoids applicable in regenerative medicine, disease modeling, and drug screening. These applications require the provision of hPSC-derived renal cells by reproducible, scalable, and efficient methods. We established a chemically defined protocol by application of Activin A, BMP4, and Retinoic acid followed by GDNF, which steered hPSCs to the renal lineage and resulted in populations of SIX2+/CITED1+ metanephric mesenchyme- (MM) and of HOXB7+/GRHL2+ ureteric bud (UB)-like cells already by 6 days. Transcriptome analysis corroborated that the PSC-derived cell types at day 8 resemble their renal vesicle and ureteric epithelial counterpart in vivo, forming tubular and glomerular renal cells 6 days later. We demonstrate that starting from hPSCs, our in vitro protocol generates a pool of nephrogenic progenitors at the renal vesicle stage, which can be further directed into specialized nephronal cell types including mesangial-, proximal tubular-, distal tubular, collecting duct epithelial cells, and podocyte precursors after 14 days. This simple and rapid method to produce renal cells from a common precursor pool in 2D culture provides the basis for scaled-up production of tailored renal cell types, which are applicable for drug testing or cell-based regenerative therapies.


Assuntos
Técnicas de Cultura de Células/métodos , Diferenciação Celular , Néfrons/citologia , Células-Tronco Pluripotentes/citologia , Ativinas/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Humanos , Néfrons/efeitos dos fármacos , Néfrons/metabolismo , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Transcriptoma/efeitos dos fármacos , Tretinoína/farmacologia
4.
Cancer Immunol Immunother ; 65(9): 1113-21, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27448806

RESUMO

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome caused by mutations of the NF1 gene and resulting dysregulation of the Ras-pathway. In addition to peripheral nerve tumors, affected tissues include the musculoskeletal and cardiovascular system. The immune system has recently been suggested as a possible modulator NF1-related phenotypes. Therefore, we determined the immune phenotype in NF1 patients and investigated its relationship with the phenotypic severity of NF1-related tumor manifestations. We quantified global leukocytes and lymphocyte subpopulations of peripheral blood from 37 NF1 patients and 21 healthy controls by flow cytometry. To associate immune phenotype with tumor phenotype, all NF1 patients underwent whole-body magnetic resonance imaging and total internal tumor volume was calculated. The immunophenotypes were compared among four NF1 groups with different total internal tumor burdens and between NF1 patients and non-NF1 subjects. We found that NF1 patients show a generalized lymphopenia. Closer analysis revealed that the CD8(+)/CD27(-) and CD8(+)/CD57(+) effector T cell fractions strongly increase in NF1 patients with low tumor load and decrease to levels below control in patients with high tumor load. Moreover, increased production of IL2, IFN-γ and TNF-α was found in T cells of NF1 patients upon phorbol-12-myristate acetate (PMA) stimulation compared to healthy controls. The data indicate that decreasing CD8(+)/CD57(+) and CD27(-) T cell fractions correspond to increasing tumor load in NF1 patients, potentially making these populations useful marker for internal tumor burden.


Assuntos
Neurofibromatose 1/imunologia , Neurofibromatose 1/patologia , Linfócitos T/classificação , Linfócitos T/imunologia , Adolescente , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia , Carga Tumoral , Adulto Jovem
5.
Ecotoxicology ; 24(5): 1064-72, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25762104

RESUMO

Eurasian otters (Lutra lutra) are endangered worldwide, but the specific cause of their decline has not been determined. This study analyzed the concentrations of potentially toxic trace elements, including As, Cd, Pb, Hg, Se, Cu, Mn, and Zn, in the liver, kidney, and lung tissues of Eurasian otters in South Korea. There were high individual variations in the tissue concentrations of all the elements analyzed. The kidneys had the highest concentrations of Cd and Se among the three tissue groups, and the livers had the highest concentrations of Cu, Mn, Zn, and Hg. The Pb and As concentrations in the livers were not significantly different from those in the kidneys, and the lungs had the lowest concentrations of all the elements analyzed. The age-related bioaccumulation of Cd and Hg was evident in the three tissue groups, and of Se in the kidneys. The Pb concentration was higher in the livers of juveniles compared with those of adults and the Zn concentration was higher in the lungs of juveniles. There were no apparent gender differences in the concentrations of the elements analyzed among the tissue groups. The Se concentration correlated with the Hg concentration in the livers and kidneys, and with the Cd concentration in the kidneys. The Hg and Cd levels correlated in the three tissue groups. The Cu and Zn levels also correlated in the livers and kidneys. In general, the element concentrations were within the ranges reported by previous studies of this species from European countries, except for Cd and Hg, the levels of which were mostly lower than those reported previously. These findings may provide baseline information to facilitate the conservation of the Eurasian otter. To the best of our knowledge, this is the first available study of trace element concentrations in the tissues of Eurasian otters from South Korea or Asian countries.


Assuntos
Lontras/fisiologia , Oligoelementos/análise , Poluentes Químicos da Água/análise , Fatores Etários , Animais , Espécies em Perigo de Extinção , Feminino , Rim/química , Fígado/química , Pulmão/química , Masculino , República da Coreia
6.
Prev Med ; 54 Suppl: S50-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22285947

RESUMO

Aging is characterized by reduced tissue and organ function, regenerative capacity, and accompanied by a decrease in tissue resident stem cell numbers and a loss of potency. The impact of aging on stem cell populations differs between tissues and depends on a number of non cell-intrinsic factors, including systemic changes associated with immune system alterations, as well as senescence related changes of the local cytoarchitecture. The latter has been studied in the context of environmental niche properties required for stem cell maintenance. Here, we will discuss the impact of the extracellular matrix (ECM) on stem cell maintenance, its changes during aging and its significance for stem cell therapy. We provide an overview on ECM components and examples of age associated remodeling of the cytoarchitecture. The interaction of stem cells with the ECM will be described and the importance of an intact and hospitable ECM for stem cell maintenance, differentiation and stem cell initiated tissue repair outlined. It is concluded that a remodeled ECM due to age related inflammation, fibrosis or oxidative stress provides an inadequate environment for endogenous regeneration or stem cell therapies. Means to provide adequate ECM for stem cell therapies and endogenous regeneration and the potential of antioxidants to prevent ECM damage and promote its repair and subsequently support regeneration are discussed.


Assuntos
Envelhecimento/metabolismo , Matriz Extracelular/metabolismo , Células-Tronco/citologia , Antioxidantes/farmacologia , Matriz Extracelular/efeitos dos fármacos , Humanos , Estresse Oxidativo/fisiologia , Transplante de Células-Tronco , Células-Tronco/metabolismo
7.
Cells ; 11(8)2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35456007

RESUMO

The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects on graft tolerance and control. In the present study, the allogeneic and autologous cellular immunity of hiPSC-derived progenitor and terminally differentiated cells were investigated in vitro. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells are both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties result from active immunomodulation and low immune visibility, which decrease during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses are not suppressed by hiPSC-derived renal cells and effectively change NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T and NK cell responses, with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune-suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings.


Assuntos
Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Células Matadoras Naturais , Ativação Linfocitária
8.
Stem Cell Investig ; 3: 13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27357481
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