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Die Mikroarchitektur der humanen Plazenta und ihre Korrelation mit dem Plazentagewicht in physiologischen Schwangerschaften
Get PDFDissecting the cell type-specific role of FKBP51 in the stress response and whole-body metabolism
Get PDFOur world is facing a pandemic of stress-related disorders, ranging from mental health to cardiovascular and metabolic diseases, and there is an urgent need for effective and selective treatments. Despite enormous efforts and decades of research, we are still far from finding targeted interventions for most psychiatric but also metabolic diseases. The identification of genetic risk factors and subsequently deciphering their tissue- and cell type-specific role in physiology is an indispensable step towards a more comprehensive understanding of the molecular mechanisms underlying these disorders. One prominent example is the co-chaperone FKBP51, which has been linked to the development of psychiatric and metabolic disorders in humans. It has been shown to be involved in a plethora of cellular signaling pathways that modulate our hormonal stress response system, the hypothalamic-pituitary-adrenal (HPA axis), and whole-body metabolism. To dissect the tissue-specific role of FKBP51 in the HPA axis, we selectively manipulated FKBP51 expression in mouse paraventricular nucleus (PVN), the master regulator of the central stress response, and assessed the behavioral and endocrine phenotypes of these animals. We were further interested in whether loss of FKBP51 in corticotrope pro-opiomelanocortin (POMC) cells in the pituitary gland (PIT) affects negative feedback control of the HPA axis and age-related dysregulation of the stress response. Both cell type-specific studies on the involvement of FKBP51 in HPA axis (re)activity revealed a beneficial effect of attenuating Fkbp5 expression, which is consistent with systemic endogenous knockout (KO) studies in rodents. To expand the existing knowledge on the role of FKBP51 in autophagy signaling, we knocked out and overexpressed (OE) the gene in the mediobasal hypothalamus (MBH), which is known for its key role in energy homeostasis and feeding behavior. Our study identified a novel group of molecular players called phosphoinositide protein family (WIPI proteins) that interact with FKBP51 to control autophagy signaling in the rodent MBH. Since the MBH is a heterogeneous structure with multiple neuronal subpopulations that all individually and synergistically contribute to shaping homeostasis, we set out to investigate the cell type-specific role of FKBP51 in steroidogenic factor 1 (Sf1) expressing neurons of the ventromedial hypothalamus (VMH) and Pomc-expressing cells of the arcuate nucleus (ARC). Intriguingly, KO of FKBP51 in these two MBH subnuclei had opposite effects on high-fat diet (HFD) induced body weight (BW) gain: KO of FKBP51 in VMH-SF1 neurons adversely affects whole-body metabolism, corresponding to an MBH-wide KO of this co-chaperone. However, attenuation of Fkbp5 expression in POMC neurons had positive effects on BW regulation under a HFD challenge. Thus, the collective results of this work highlight the importance of cell type-specific studies on the role of FKBP51 in homeostatic control and pave the way for future pharmacological intervention studies
Qualität und Langlebigkeit von Implantaten mit direkt verschraubten Einzelzahnkronen vor und nach künstlicher Alterung
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Locoregional heterogeneity of glioblastoma entails pro- or antitumorigenic effects of tumor associated mesenchymal stem cells
Get PDFAmong other cell lines of the tumor microenvironment, mesenchymal stem cells play an important role in glioma progression. However, many diverging aspects were shown throughout the complex interaction between mesenchymal stem cells and tumor cells. The first part of this work investigated in the migration of injected mesenchymal stem cells in glioblastoma. Furthermore, this study aimed to model one pathologically relevant aspect of the in vivo interaction between mesenchymal stem cells and glioma cells under simplified in vitro conditions in order to analyze a potential effect on the viability of glioma cells.
First, mice were intracranially inoculated with glioma cells. Once the tumor had grown for 58 days, mesenchymal stem cells were injected into the brain into the main tumor mass. After sacrificing the mice, brain sections were analyzed with regards to the mesenchymal stem cells location and blood-brain barrier integrity in glioma. Furthermore, an in vitro proliferation assay was performed studying glioma cells viability under serum-free mesenchymal stem cell conditioned medium.
The in vivo experiment shows migration of mesenchymal stem cells to invasive parts of the tumor. It was demonstrated that in these regions the blood-brain barrier is widely intact. Hence, serum-derived factors larger than the size of 70 kDa do not reach the structures where mesenchymal stem cells reside. Consequently, this serum-free situation was modeled in an in vitro proliferation assay. Serum-free medium, which was conditioned by mesenchymal stem cells, enhances viability in two lines of glioma stem cells even under conditions of chemotherapy.
This paper adds to our understanding of the complex interaction between mesenchymal stem cells and glioma cells. The results of the study provide evidence for mesenchymal stem cells tropism for invasive regions of glioblastoma. These invasive regions remain in the brain after neurosurgery, representing the source of tumor relapse. Taken together, these encouraging results suggest that mesenchymal stem cells are able to support tumor relapse formation by improving viability of glioma cells even under conditions of chemotherapy. This makes mesenchymal stem cells and their interaction with glioblastoma promising potential therapeutical targets to evaluate in glioblastoma therapy in the future
Die Rolle des thrombozytären Chemokins CXCL12 in der arteriellen Thrombose und Atherosklerose
Get PDFClinical data patterns supporting differential diagnosis of recent onset of depression and clinical high risk for psychosis
Get PDFObesity and circulating markers of low-grade systemic inflammation: An exploratory study using population-based data
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