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Christ B.,University of Leipzig | Christ B.,Translational Center for Regenerative Medicine | Bruckner S.,University of Leipzig
Frontiers in Physiology | Year: 2012

Without therapeutic intervention acute liver failure (ALF) is the consequence of a progredient destruction of the liver parenchyma due to metabolic exhaustion of the hepatocytes. Perivenous hepatocytes are responsible for the detoxification of noxious compounds via the cytochrome P450 enzyme system. Liver transplantation is the only remaining therapeutic option in the end-stage of the disease. Assuming that metabolic capacity could be provided by healthy hepatocytes and thus substitute for the genuine parenchymal cells hepatocyte transplantation since quite some time is considered to be an alternative to whole liver transplantation. While this hypothesis achieved proof-of-concept in animal trials clinical breakthrough is still awaiting success, the reasons of which are ongoing matter of debate. In recent times mesenchymal stem cells (MSC) came into focus as a transplantable cell source to treat ALF. Interestingly, as demonstrated in various rodent animal models their mode of action is rather based on trophic support of hepatocytes remaining in the damaged host parenchyma rather than substitution of tissue loss. Mechanistically, either direct or indirect paracrine effects from the transplanted cells acting pro-proliferative, anti-apoptotic, and anti-inflammatory seem to trigger the regenerative response of the residual healthy hepatocytes in the otherwise lethally injured liver parenchyma. Thus, allogeneic MSC may be the best choice for the treatment of ALF taking advantage of their short-term benefit to sustain the critical phase of the acute insult avoiding long-term immunosuppression. © 2012 Christ and Brückner.


Wagner D.-C.,Fraunhofer Institute for Cell Therapy and Immunology | Riegelsberger U.M.,Fraunhofer Institute for Cell Therapy and Immunology | Michalk S.,Fraunhofer Institute for Cell Therapy and Immunology | Hartig W.,University of Leipzig | And 3 more authors.
Brain Research | Year: 2011

Cleaved caspase-3 (CC3) is well known as an executioner protease of apoptosis following brain ischemia. However, an increasing body of evidence suggests several non-apoptotic functions of CC3. To improve our understanding of the relation between cell death-related and non-adverse effects of postischemic caspase-3 activation, we examined the spatiotemporal distribution and identity of CC3-positive cells at days 2, 3 and 4 after permanent middle cerebral artery occlusion in rats. The lacking colocalization of CC3 and TUNEL staining indicated, that CC3 expression was predominantly non-apoptotic. Nuclear CC3 expression was frequently found to be colocalized with GFAP-positive astrocytes within the tissue adjacent to the infarct, whereas cytoplasmatic CC3 expression occurred solely in the lesion. Multiple fluorescence labeling revealed costaining of cytoplasmatic CC3 with markers directed against astrocytes, macrophages/microglia and supposedly pericytes. Our findings suggest that CC3 expression was predominantly associated with cellular responses to stroke such as reactive astrogliosis and the infiltration of macrophages. © 2011 Elsevier B.V. All rights reserved.


Weise G.,University of Wurzburg | Weise G.,Fraunhofer Institute for Cell Therapy and Immunology | Weise G.,Translational Center for Regenerative Medicine | Stoll G.,University of Wurzburg
Frontiers in Neurology | Year: 2012

Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate.We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients. © 2012 Weise and Stoll.


Christ B.,Applied Molecular Hepatology Laboratory | Christ B.,Translational Center for Regenerative Medicine | Stock P.,Applied Molecular Hepatology Laboratory
Frontiers in Immunology | Year: 2012

Mesenchymal stem cells represent an alternate cell source to substitute for primary hepa- tocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerat- ing livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action. © 2012 Christ and Stock.


Tarnok A.,University of Leipzig | Pierzchalski A.,Translational Center for Regenerative Medicine | Valet G.,Max Planck Institute For Biochemie
Current Medicinal Chemistry | Year: 2010

It takes about 10 to 15 years and roughly 800 mln $ to bring a new drug to the market. Only 10% of drug mole- cules entering clinical trials succeed and only 3 out of 10 drugs generate enough profit to pay back for the investment. Drug targets may be searched by hypothesis driven modeling of molecular networks within and between cells by systems biology. However, there is the potential to simplify the search for new drugs and drug targets by an initial top-down cytomics phase. The cytomics approach i) requires no detailed a-priori knowledge on mechanisms of drug activity or complex diseases, ii) is hypothesis driven for the investigated parameters (genome, transcriptome, proteome, metabolome a.o.) and iii) is hypothesis-free for data analysis. Moreover it iv) carries the potential to uncover unknown molecular interrelations as a prerequisite for later new hypothesis driven modeling and research strategies. A set of discriminatory parameter patterns (molecular hotspots) describing the cellular model (mechanism of drug action) can be identified by differential molecular cell phenotyping. Hereby, the immediate modeling of existing complexities by bottom-up oriented systems biology is avoided. The review focuses on the fast technological developments of molecular single cell analysis in recent years. They com- prise a multitude of sensitive new molecular markers as well as various new image and flow cytometric high-content screening methods as facilitators of the cytomics concept. New bioinformatic tools enable the extraction of relevant mo- lecular hotspots in description of cellular models, being required for the subsequent molecular reverse engineering phase by systems biology. © 2010 Bentham Science Publishers Ltd.

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