Anästhesiologie
AG Dr. Kleger
Principal Investigator:
|
Dr. rer. med. Alexander Kleger, PhD
|
Universitätsklinikum Ulm
Zentrum für Innere Medizin
Klinik für Innere Medizin I
Max-Planck-Research Group on Stem Cell Aging, Ulm University
Albert-Einstein-Allee 23
89081 Ulm
Tel.: +49 731-500-44728
Fax: +49 731-500-44665
Current Members:
Dr. med. Martin Müller, MD
martin.mueller[at]uniklinik-ulm.de
Tel.: + 49 731-500-44711
Dr. med. Lukas Perkhofer, MD
lukas.perkhofer[at]uniklinik-ulm.de
Tel.: + 49 731-500-44769
Ralf Köhntop, Technician
ralf.koehntop[at]uniklinik-ulm.de
Tel.: + 49 731-500-44660
Ronan Russell, PhD
Clair Weidgang, Medical Thesis Student
clair.weidgang[at]uni-ulm.de
Alumni:
Christiane Loebnitz, Medical Thesis Student
christiane.loebnitz[at]gmx.de
Michael Tischendorf, Medical Thesis Student
michael.tischendorf[at]uni-ulm.de
Join our Lab:
PhD and MD student positions available
Applications in English or German are welcome: alexander.kleger[at]uni-ulm.de
Publications:
2012
Liver progenitor cells exhibit BAF complex dependent increases in reprogramming capacity compared to differentiated liver cells. Kleger A1,2, Madaddalkar P1, Katz SF, Lechel A, Ju JY, Loya K, Lin Q, Hartmann D, Liebau S, Kraus J, Cantz T, Kestler HA, Zaehres H, Schöler H,Rudolph KL2. 1 equal contribution. 2 corresponding authors. Gastroenterology, in press.
The Potential of iPS cells in Synucleinopathy Research. Linta L, Stockmann M, Boeckers T, Kleger A, Liebau S. Stem Cells Int., in press.
2011
Developmental and functional nature of human iPSC derived motoneurons. Stockmann M, Linta L, Föhr KJ, Boeckers A, Ludolph AC, Kuh GF, Udvardi PT, Proepper C, Storch A, Kleger A, Liebau S, Boeckers TM. Stem Cell Reviews, in press.
Ca2+-activated K+-Channels - New Tools to induce Cardiac Commitment
from Pluripotent Stem Cells in Mice and Men.
Müller M, Stockmann M, Malan D, Wolheim A, Tischendorf M, Linta L, Katz SF, Lin Q, Latz S, Brunner C, Wobus AM, Zenke M, Wartenberg M, Boeckers TB, von Wichert G, Fleischmann BF, Liebau S, Kleger A
Stem Cell Reviews, in press.
An Inducible Expression System of the Calcium-Activated Potassium Channel 4 to Study the Differential Impact on Embryonic Stem Cells.
Liebau S, Tischendorf M, Ansorge D, Linta L, Stockmann M, Weidgang C, Iacovino M, Boeckers T, von Wichert G, Kyba M, Kleger A.
Stem Cells Int. 2011;2011:456815. Epub 2011 Sep 15.
The impact of bioactive lipids on cardiovascular development.
Kleger A, Liebau S, Lin Q, von Wichert G, Seufferlein T.
Stem Cells Int. 2011;2011:916180. Epub 2011 Aug 2.
Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation.
Azoitei N, Kleger A, Schoo N, Thal DR, Brunner C, Pusapati GV, Filatova A, Genze F, Möller P, Acker T, Kuefer R, Van Lint J, Baust H, Adler G, Seufferlein T.
Neuro Oncol. 2011 Jul;13(7):710-24.
Rat Embryonic Fibroblasts Improve Reprogramming of Human Keratinocytes into Induced Pluripotent Stem Cells.
Linta L, Stockmann M, Kleinhans KN, Böckers A, Storch A, Zaehres H, Lin Q, Barbi G, Böckers TM, Kleger A, Liebau S.
Stem Cells Dev. 2011 Aug 5. [Epub ahead of print]
Telomerase gene mutations are associated with cirrhosis formation.
Hartmann D, Srivastava U, Thaler M, Kleinhans KN, N'kontchou G, Scheffold A, Bauer K, Kratzer RF, Kloos N, Katz SF, Song Z, Begus-Nahrmann Y, Kleger A, von Figura G, Strnad P, Lechel A, Günes C, Potthoff A, Deterding K, Wedemeyer H, Ju Z, Song G, Xiao F, Gillen S, Schrezenmeier H, Mertens T, Ziol M, Friess H, Jarek M, Manns MP, Beaugrand M, Rudolph KL.
Hepatology. 2011 May;53(5):1608-17. doi: 10.1002/hep.24217.
An SK3 channel/nWASP/Abi-1 complex is involved in early neurogenesis.
Liebau S, Steinestel J, Linta L, Kleger A, Storch A, Schoen M, Steinestel K, Proepper C, Bockmann J, Schmeisser MJ, Boeckers TM.
PLoS One. 2011 Mar 25;6(3):e18148.
Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice.
von Figura G, Wagner M, Nalapareddy K, Hartmann D, Kleger A, Guachalla LM, Rolyan H, Adler G, Rudolph KL.
PLoS One. 2011 Feb 22;6(2):e17122.
Protein kinase D2 is an essential regulator of murine myoblast differentiation.
Kleger A, Loebnitz C, Pusapati GV, Armacki M, Müller M, Tümpel S, Illing A, Hartmann D, Brunner C, Liebau S, Rudolph KL, Adler G, Seufferlein T.
PLoS One. 2011 Jan 27;6(1):e14599.
2010
Modulation of calcium-activated potassium channels induces cardiogenesis of pluripotent stem cells and enrichment of pacemaker-like cells.
Kleger A, Seufferlein T, Malan D, Tischendorf M, Storch A, Wolheim A, Latz S, Protze S, Porzner M, Proepper C, Brunner C, Katz SF, Varma Pusapati G, Bullinger L, Franz WM, Koehntop R, Giehl K, Spyrantis A, Wittekindt O, Lin Q, Zenke M, Fleischmann BK, Wartenberg M, Wobus AM, Boeckers TM, Liebau S.
Circulation. 2010 Nov 2;122(18):1823-36.
Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours.
Azoitei N, Pusapati GV, Kleger A, Möller P, Küfer R, Genze F, Wagner M, van Lint J, Carmeliet P, Adler G, Seufferlein T.
Gut. 2010 Oct;59(10):1316-30. Epub 2010 Aug 23.
2006 - 2009
First reported case of disease: peliosis hepatis as cardinal symptom of Hodgkin's lymphoma.
Kleger A, Bommer M, Kunze M, Klaus J, Leithaeuser F, Wegener M, Adler G, Dikopoulos N.
Oncologist. 2009 Nov;14(11):1088-94. Epub 2009 Nov 4.
The bioactive lipid sphingosylphosphorylcholine induces differentiation of mouse embryonic stem cells and human promyelocytic leukaemia cells.
Kleger A, Busch T, Liebau S, Prelle K, Paschke S, Beil M, Rolletschek A, Wobus A, Wolf E, Adler G, Seufferlein T.
Cell Signal. 2007 Feb;19(2):367-77. Epub 2006 Jul 28.
Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells.
Hermann A, Maisel M, Liebau S, Gerlach M, Kleger A, Schwarz J, Kim KS, Antoniadis G, Lerche H, Storch A.
J Neurochem. 2006 Jul;98(2):629-40. Epub 2006 Jun 12.
Reviewing activities:
- Stem Cells
- PLos One
- Stem Cells and Development
- Cardiovascular Research
- Stem Cells International
- Circulation Research
Editorial board memberships:
- American Journal of Stem Cells
Main Interest of the Lab – stem cells:
Embryonic stem cells (ES cells) are characterized by unlimited self renewing capacity and the capability differentiate into all tissue types. ES cells have been isolated for the first time in 1981 by Evans and Kaufmann from mouse embryos, thereby they have created a new platform for in vitro differentiation of different tissue types and established new perspectives in terms of generation of transgenic animals. Less than two decades later Thomson et al. described the generation of ES cells from human embyos (1998). In 2006, the lab of Shinya Yamanaka pioneered the field by the generation of induced pluripotent stem cells upon expression of certain transcription factors.
My lab focuses on the differentiation of different stem cell types, in particular murine ES cells to certain lineages. Thereby we use ES cells as a tool to dissect the impact of chemical compounds, physiological signaling peptides or genes on in vitro differentiation.
A: Calcium activated potassium channels and their functional role during ES cell differentiation and during embryonic development
Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca2+-activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. We are investigating their impact on the differentiation of pluripotent cells towards different lineages. Previous work of the lab has shown that SKCa activation drives the fate of pluripotent cells towards mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. Currently, we try to dissect the responsible signalling pathway being and to optimize these protocols in induced pluripotent stem cells.
ES cell differentiation upon SKCa activation as shown by the loss of Oct4 protein
Cardiac pacemaker cell (Hcn4 positive) generated from ES cells upon SKCa activation
B. Engineering transgenic embryonic stem cells to investigate the functional role of different protein kinases and transcription factors during stem cell differentiation
ES cells represent a unique model for investigation of developmental processes, especially because of their ability to differentiate into every type of tissue. Via forced but triggered expression of certain genes, it is possible to explore their impact on the differentiation properties of ES cells. Thereby we make use of a unique system which has been kindly provided to the lab by Michael Kyba, University of Minnesota, namely the A2lox.cre ES cell line. The cell line allows the inducible expression of “genes of interest” after gene targeting into the HPRT locus. Thereby it is possible to either generate knock in ES cells or knock in mice.
Dox-inducible expression of GFP after gene targeting into the HPRT Locus of A2lox.cre ES-cells
Chimeric mouse generated after blastocyst injection of A2lox ES cells harbouring a knock in cassette
C: Regulation of skeletal muscle differentiation
Muscle differentiation occurs through the activation of quiescent satellite cells whose progeny proliferate, differentiate, and fuse to generate new myofibers. A defined pattern of myogenic transcription factors is orchestrated during this process and is regulated via distinct signaling cascades involving various intracellular signaling pathways, including members of the protein kinase C or phospholipase D families. The protein kinase D (PKD) isoenzymes PKD1, -2, and -3, are prominent downstream targets of PKCs and PLDs in various biological systems and could hence play a role in muscle differentiation. In a present study, we are using the mouse satellite cell line (C2C12) as an in vitro model to investigate the role of PKDs in muscle stem cell differentiation.
Depletion of PKD2 diminishes differentiation of skeletal muscle myoblast
D. Reprogramming of different liver cell types to induced pluripotent stem cells
Induced pluripotent stem cells can be generated from somatic cells by the overexpression of a certain set of transcription factors, such as Oct4, Sox2, Klf4 and c-Myc (OSKM). This has also been demonstrated for hepatocytes. So far, induced pluripotent stem cells (iPS cells) have been generated from several tissues in different organisms such as mice, rabbits, monkeys and humans. However, generation of iPS cells is limited due to low reprogramming efficiency (<1%) and long duration (several weeks) of reprogramming in contrast to nuclear transfer or cell fusion. The identification of subpopulations of organ cells that are amenable to high efficient reprogramming could improve the use of iPS cells for translational research and could increase the mechanistic understanding of the reprogramming process itself. Recently, hepatic progenitor populations have been identified in fetal and adult mouse liver. A subset of these cells exhibits a bipotent differentiation potential in cell culture. However, the reprogramming efficiency of liver progenitor cell compared to differentiated liver cells has not been investigated. Currently we are studying in close collaboration with Prof. Rudolph, Max-Planck-Research Department on Stem Cell Aging, whether liver progenitors are more amenable to cellular reprogramming than differentiated cell types.
Formation of two iPS cell colonies out of liver progenitor cells derived from Oct4-EGFP reporter mice.
E. Generation of exocrine Pancreas from ES and iPS cells from both murine and human origin
Spontaneous differentiation of embryonic stem cells (ES cells) provides limited access to exocrine pancreatic cells. The produced amounts are barely enough for research study and far short of the numbers needed for therapeutic application. One strategy to increase the efficiency of exocrine pancreatic cell formation is to mimic embryonic development by exposing ES cells and their derivatives to factors that they would normally encounter in vivo. The starting point for this strategy is differentiating ES cells into definitive endoderm. The molecular mechanisms controlling cell fate determination and subsequent proliferation, however, are poorly understood. Unlike endocrine cells, less is known about exocrine cell specification. We are investigating new exocrine cell determinant genes and the effects of their overexpression on cellular differentiation on transcriptional level, protein-biosynthesis and phenotype.
Cooperation Partners:
Dr. med. Stefan Liebau, Institute for Anatomy and Cell Biology, University of Ulm, Germany
Prof. Karl Lenhard Rudolph, Max-Planck-Research Department on Stem Cell Aging, Ulm University, Germany
Prof. Bernd Fleischmann, Institute of Physiology I, Life and Brain Center, University of Bonn, Germany
Prof. Maria Wartenberg, Department of Internal Medicine I, University of Jena, Germany
Prof. Martin Zenke, Institute for Biomedical Engineering, Department of Cell Biology, Aachen, Germany
Prof. Anna Wobus, Leibniz Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany
Prof. Eckhard Wolf, Gene Center Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
Prof. Thomas Seufferlein, Department of Internal Medicine I, University of Halle, Germany
nach oben