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PD Dr. Franz-Josef Müller is the head of the Laboratory for Integrative Biology.
We are experimentally studying fundamental mechanisms underlying pluripotent stem cell function, neural differentiation and dysfunction in neuropsychiatric disorders.
Towards this overarching goal our approach is highly multidisciplinary and we are employing a wide range of methods and technologies - ranging from mathematical modeling of biological systems to genetic and epigenetic engineering of induced pluripotent stem cells from patients suffering from epigenetically triggered, pervasive developmental disorders, neurodegeneration or psychosis. Our basic research work on elucidating the mechanistic underpinnings of stem cell biology has resulted in online resources and tools serving the wider stem cell research community
- the StemCellMatrix and PluriTest.
We work with a number of groups locally, nationally and internationally including:
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Reiner Siebert and Ole Ammerpol at the Institute for Human Genetics, UKSH Campus Kiel, Susanne A. Schneider, Department for Neurology, UKSH Campus Kiel, Thomas C. Bosch at the Department for Zoology at the Christian-Albrechts University in Kiel, Phil Gribbon and Ole Pleß at the European ScreeningPort, Hamburg, Nils Ole Schmidt at the Department for Neurosurgery UKE, Hamburg-Eppendorf, Philipp Koch at the Life and Brain Center, Bonn, Bernhard Horsthemke at the Institute for Human Genetics, University Hospital Duisburg-Essen, Andreas Schuppert and Bernhard Schult at the Joint Research Center for Computational Biomedicine, AICES/RTWT Aachen, Ben MacArthur at the University of Southampton, UK, Jeanne Loring at the Scripps Research Institute, La Jolla, CA/USA.

Please find some more information on our research environment, past, present and future work following the links on this page.
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The LIB is located at the Zentrum für Integrative Psychiatrie Campus Kiel, a institution which also serves the LIB as administrative body.
The LIB is part of the University Hospital Schleswig Holstein, one of the largest research hospitals in Europe.
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Several of our projects are focussed on the systems wide underpinnings of pluripotency and differentiation. Only this global approach can provide a reliable basis for interpreting results stemming from iPSC based models of human disorders.
Consequently we pursue a fundamental approach to biological phenomena beyond the mere application of established biotechnological methods and thus lets us strive to reach a better understanding of the biologic underpinnings of pluripotency and differentiation.

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Understanding epigenetic states with quantitative and network reconstruction approaches

With biology having arrived in the high-through put era, diverse molecular network realms are actively being quantified with the ultimate goal to eventually exhaustively map all regulatory interactions (for example, all functional PPIs or TF-DNA interactions). Networks can build a bridge between observable variables without direct mechanistical relevance and “hidden” variables, which could be driving a specific biological phenomenon such as defined states or dynamic trajectories on the epigenetic landscape. We have found that a particularly successful strategy is to use statistical learning theory as a stringent framework for comparative evaluation of alternative network inference methods. This pragmatic and evolutionary approach can be adopted in several biological realms and makes optimal use of todays sophisticated network modeling methodologies.
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Modeling human disorders in vitro with induced pluripotent stem cells.

We are generating patient-derived induced pluripotent stem cell lines from neuro-psychiatric disorders, including inborn errors of neural metabolism, single- and multi- locus DNA-methylation disorders as well as rare Mendelian forms of Parkinsons Disease. The resulting cell lines are being in depth characterized following established protocols as well as bioinformatic approaches pioneered by us. We are using the CRISPR/Cas9 technology to generate stable transgenic iPSC "sensor lines" and we are using DNA-binder (TALE and CRISPR/Cas9) mediated genome and epigenome editing for the functional exploration of patient-specific in vitro phenotypes in neural cells derived from our growing library of sensor/patient-specific lines (See also next section).

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Assessing pluripotency and other epigenetically defined, dynamic cellular states

We have developed
computational methods to identify and in depth characterized cellular sets based on genome wide gene expression profiles. Important to us was to bring these tools into the hands of researchers world wide as there is an unmet need in reliable methods for e.g. identifying high-quality human pluripotent stem cells without costly animal experiments (like the teratoma assay). We are currently expanding the scope of such tools by integrating new data types, increasing the depth of the individual analysis by allowing for more detailed metrics on cytobands, imprinted regions and computationally defined pathways predictive for differentiation propensity.
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Our research involves the generation and differentiation of induced pluripotent stem cells from human subjects and mice. The LIB also employs human embryonic stem cells as gold standard for validating findings in iPSC. We are characterizing our experiments mainly with genome-wide profiling methods, such as microarray-based DNA-methylation and RNA-seq profiling.
With this enabling toolset in place, we are studying epigenetically and genetically triggered pathophysiologic process in vitro and engineer iPSC-derived somatic cells as potential gene therapy vectors.


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Induced pluripotent stem cell lines from patients with imprinting disorders

We have generated and are currently functionally studying several hiPSC lines from imprinting syndrome patients. We have also established several iPSC lines from patients with novel global multi-locus methylation syndromes. This work is done in collaboration with the Horsthemke group in Essen and the Siebert group in Kiel and is part of the Germany-wide consortium "Diseases caused by imprinting defects: clinical spectrum and pathogenetic mechanisms" funded by the Bundesministerium für Bildung und Forschung (BMBF).

We are thankful for the patients' and their families' ongoing support
and willingness to participate in this important research.


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Induced pluripotent stem cell lines from patients with neuropsychiatric disorders

We are studying the pathobiology of monogenic forms neuropsychiatric disorders in cells differentiated from hiPSC. Genetically engineered, isogenic stem cell lines differing only in a single gene variant allow for comparison of mutant and wild type alleles in the same genetic background. This isolates the causative mutation from other genetic factors. Thereby, isogenic lines can provide substantial proof that a particular genetic variation is the cause of a specific disease. This fascinating work is done in collaboration with
Susanne Schneider from the UKSH Department for Neurology in Kiel.

Here as well, we are grateful for the patients' and their families' participation and openness to donate skin punch biopsies for the generation of patient-specific induced pluripotent stem cells.

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Neural stem cells as gene therapy vectors in brain malignancy

Neural stem/progenitor cells (NSC) display inherent pathotropic properties that can be exploited for targeted delivery of therapeutic genes to invasive malignancies in the central nervous system. Based on various established in vitro and in vivo models the migration, tumor homing and therapeutic efficiency of genetically-modified NSC using the HSV1-thymidinkinase/ganciclovir-system are assessed.

This work represents a close collaboration with Nils Ole Schmidt at the Department for Neurosurgery UKE, Hamburg-Eppendorf and it is funded by the DFG.

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We have been granted research project funding from several national public and privat science funding organizations .

Competitively acquired funding, currently ongoing work

Preclinical development of an autologous stem-cell based gene therapy for the treatment of malignant brain tumors,
2014 - 2017
with N. Schmidt, UKE Hamburg
Imprinting Disorders WP6: Multi-locus methylation defects: association with TNDM and SGA, genome-wide characterization and modeling in iPSC
2012 - 2015
with R. Siebert, UKSH Kiel
e:Bio MMML-MYC-SYS WP1: Modeling of mechanisms leading to MYC translocations: Evidence for iPSC-like stemness in Burkitt-lymphoma?
2013 - 2016
with R. Siebert, UKSH Kiel
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Induced pluripotent stem cells as model for rare mongenic forms of neurodegenerative disorders
2014
with S. Schneider, UKSH Kiel
Core laboratory ISCI 3.2: Provision of PluriTest analyses to the International Stem Cell Initiative 3.2
2013 - 2015
Cluster of Excellence Research Area II: Somatic and Epigenetic Determination of Cellular Destiny
2013 - 2017
with
O. Ammerpol, UKSH Kiel
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Competitively acquired funding, past projects

Genome wide quality control of pluripotent stem cells
2009 - 2010
Molecular analysis of brain development in diverse transgenic reporter mice strains
2009
Analysis of microglia in the GFP-transgene Pu1-KO mice
2007
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Derivation of human neural precursor cells from epilepsy patients
2006
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Our lab consists of scientists at all levels of experience and training. The LIB has been slowly growing since the beginning of the stem cell efforts at the Zentrum für Integrative Psychiatrie in 2005. We focus on our core competencies in stem cell biology and bioinformatic modeling. We maintain highest work and training standards by being very selective because of our goal - sustained personal and professional development for all lab members.
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Here we provide links to online resources and software that we have set up for our projects and published studies. Also, here we provide files from our manuscripts for download that are frequently requested and/or were not part of the supplementary materials of the respective manuscripts.
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Sorry, but we're still working on this section!
If there his something you would like us to post from our previous work her, please drop us a line under the contact info at the bottom of this site.
Thank you very much for your patience!
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WORKING ON RIGHT NOW




Stumpf PS, Smith R, Ridden S, Bram, Müller FJ, MacArthur B. In preparation.

Wagener R, Lenz M, Schuldt BM, Lenz I, Schuppert A, Siebert R, Müller FJ. In preparation.

Brändl B, Böhnke L, Müller FJ. PluriTest: Qualification of pluripotent stem cells with systems biology approaches. In preparation.

Brändl B, Schneider
SA, Loring JF, Hardy J, Gribbon P, Müller F-J. Stem cell reprogramming: basic implications and future perspective for movement disorders. In revision.



2014


Müller F-J, Loring JF. Network biology: A compass for stem-cell differentiation. Nature. 2014 Sep 25;513(7519):498–9. LINK

Schott JW, Hoffmann D, Maetzig T, Müller F-J, Steinemann D, Zychlinski D, et al. Improved retroviral episome transfer of transcription factors enables sustained cell fate modification. Gene Ther. 2014 Aug 7. LINK

Blurton-Jones M, Spencer B, Michael S, Castello NA, Agazaryan AA, Davis JL, Müller F-J, Loring JF, Masliah E, LaFerla FM. Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther. 2014;5(2):46. LINK



2013

Lenz M, Schuldt BM, Müller F-J, Schuppert A. PhysioSpace: relating gene expression experiments from heterogeneous sources using shared physiological processes. PLoS ONE 2013;8(10):e77627.

Buta C, David R, Dressel R, Emgård M, Fuchs C, Gross U, Healy L, Hescheler J, Kolar R, Martin U, Mikkers H, Müller F-J, Schneider RK, Seiler AEM, Spielmann H, Weitzer G. Reconsidering pluripotency tests: Do we still need teratoma assays?
Stem Cell Res. 2013 Jul;11(1):552–62.

Robicsek O, Karry R, Petit I, Salman Kesner N, Müller FJ, Klein E, Aberdam D, Ben-Shachar D. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients.
Mol. Psychiatry. 2013 Jun 4.

Dambrot C, van de Pas S, van Zijl L, Brändl B, Wang JW, Schalij MJ, Hoeben RC, Atsma DE, Mikkers HM, Mummery CL, Freund C. Polycistronic lentivirus induced pluripotent stem cells from skin biopsies after long term storage, blood outgrowth endothelial cells and cells from milk teeth.
Differentiation. 2013 Feb;85(3):101–9.

Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, Zhou H, Aberdam D, Petit I. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.
Proc Natl Acad Sci USA. 2013 Feb 5;110(6):2152–6.

Schuldt BM, Guhr A, Lenz M, Kobold S, MacArthur BD, Schuppert A, Löser P, Müller FJ. Power-laws and the use of pluripotent stem cell lines.
PLoS ONE. 2013;8(1):e52068.


2012

Löser P, Kobold S, Guhr A, Müller F-J, Kurtz A. Scope and impact of international research in human pluripotent stem cells. Stem Cell Rev. 2012 Dec;8(4):1048–55.

MacArthur BD, Sevilla A, Lenz M, Müller FJ, Schuldt BM, Schuppert AA, Ridden SJ, Stumpf PS, Fidalgo M, Ma'ayan A, Wang J, Lemischka IR. Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity.
Nat. Cell Biol. 2012 Oct 28;14(11):1139–47.

Müller F-J, Brändl B, Loring JF. Assessment of human pluripotent stem cells with PluriTest. Cambridge (MA): StemBook, Harvard Stem Cell Institute; 2012.

Goldmann JE, Schuldt BM, Lenz M, Müller F-J. PluriTest molecular diagnostic assay for pluripotency in human stem cells. In: Loring JF, Peterson SE, editors. Human stem cell manual (Second Edition). New York: Academic Press; 2012. p. 293–311.

Koch P, Müller F-J, Brüstle O. Differentiation of Human Pluripotent Stem Cells into Neural Precursors. In: Loring JF, Peterson SE, editors. Human Stem Cell Manual (Second Edition). New York: Academic Press; 2012. p. 375–84.

Nazor KL, Altun G, Lynch C, Tran H, Harness JV, Slavin I, Garitaonandia I, Müller FJ, Wang Y-C, Boscolo FS, Fakunle E, Dumevska B, Lee S, Park H-S, Olee T, D'Lima DD, Semechkin R, Parast MM, Galat V, Laslett AL, Schmidt U, Keirstead HS, Loring JF, Laurent LC. Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives.
Cell Stem Cell. 2012 May 4;10(5):620–34.

Laedewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller F-J, Koch P, Brüstle O. Small molecules enable highly efficient neuronal conversion of human fibroblasts.
Nat Methods. 2012 Apr 8;:1–7.



2011


Schuldt B, Müller F-J, Schuppert A. What can networks do for you? Basic concepts of stem cell network analysis. In: MacArthur B, Ma'yan A, editors. Network Analysis in Systems Biology. New York: Springer; 2011.

Williams R, Schuldt BM, Müller F-J. A guide to stem cell identification: Progress and challenges in system-wide predictive testing with complex biomarkers.
Bioessays 2011;33.

Schuldt B, Lin Q, Müller FJ, Loring J. Basic approaches to gene expression analysis of stem cells by microarrays.
Methods Mol Biol 2011;767:269-82.

Müller, F. J. and A. Schuppert (2011). "Few inputs can reprogram biological networks."
Nature 478(7369): E4; discussion E4-5.

Müller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, Danner S, Goldmann JE, Herbst A, Schmidt NO, Aldenhoff JB, Laurent LC, Loring JF. A bioinformatic assay for pluripotency in human cells.
Nature methods 2011;8:315-7.

Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R, Galat V, Gottesfeld J, Izpisua Belmonte JC, Murry C, Keirstead HS, Park HS, Schmidt U, Laslett AL, Müller FJ, Nievergelt CM, Shamir R, Loring JF. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture.
Cell Stem Cell 2011;8:106-18.



2010


Schönfeld R, Moenich N, Müller FJ, Lehmann W, Leplow B. Search strategies in a human water maze analogue analyzed with automatic classification methods. Behav Brain Res 2010;208:169-77.

Hansen K, Müller FJ, Messing M, Zeigler F, Loring JF, Lamszus K, Westphal M, Schmidt NO. A 3-dimensional extracellular matrix as a delivery system for the transplantation of glioma-targeting neural stem/progenitor cells.
Neuro-oncology 2010;12:645 - 54.

Müller FJ, Loring JF, Baier PC. Reflections on the use of stem cells for restoring neurodegenerative damage In: Zerovnik E, Markic O, Ule A, eds.
Philosophical insights about modern science. New York: Nova Science Publishers, Inc.; 2010:89-108.

Bartsch T, Schönfeld R, Müller FJ, Alfke K, Leplow B, Aldenhoff J, Deuschl G, Koch JM. Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory.
Science 2010;328:1412-5.

Müller FJ, Goldmann J, Loser P, Loring JF. A call to standardize teratoma assays used to define human pluripotent cell lines.
Cell Stem Cell 2010;6:412-4.



2009


Cavalier C, Müller FJ. Pluripotent Stem Cell Procurement for Drug Discovery. Touch Briefings: Drug Discovery 2009;6.

Müller FJ, Loring JF, Aldenhoff JB, Gribbon P. Pathway-based target identification and validation in stem cells.
Screening 2009;4:2-3.

Schmidt NO, Koeder D, Messing M, Müller FJ, Aboody KS, Kim SU, Black PM, Carroll RS, Westphal M, Lamszus K. Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche.
Brain Res 2009;1268:24-37.

Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease.
Proc Natl Acad Sci U S A 2009;106:13594-9.



2008


Lee JP, McKercher S, Müller FJ, Snyder EY. Neural stem cell transplantation in mouse brain. Curr Protoc Neurosci 2008;Chapter 3:Unit 3 10.

Müller FJ, Laurent LC, Kostka D, Ulitsky I, Williams R, Lu C, Park IH, Rao MS, Shamir R, Schwartz PH, Schmidt NO, Loring JF. Regulatory networks define phenotypic classes of human stem cell lines.
Nature 2008;455:401-5.

Lee JP, McKercher SR, Müller FJ, Loring JF, Snyder EY. Neural Stem Cells and CNS diseases. In:
Encyclopedia of Neuroscience. 4 ed. Amsterdam: Elsevier; 2008:229-37.

Schwartz PH, Brick DJ, Stover AE, Loring JF, Müller FJ. Differentiation of neural lineage cells from human pluripotent stem cells.
Methods 2008;45:142-58.

Laurent LC, Chen J, Ulitsky I, Müller FJ, Lu C, Shamir R, Fan JB, Loring JF. Comprehensive microRNA profiling reveals a unique human embryonic stem cell signature dominated by a single seed sequence.
Stem Cells 2008;26:1506-16.



2007


Lee, J. P., M. Jeyakumar, R. Gonzalez, H. Takahashi, P. J. Lee, R. C. Baek, D. Clark, H. Rose, G. Fu, J. Clarke, S. McKercher, J. Meerloo, F. J. Müller, K. I. Park, T. D. Butters, R. A. Dwek, P. Schwartz, G. Tong, D. Wenger, S. A. Lipton, T. N. Seyfried, F. M. Platt and E. Y. Snyder (2007). "Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease." Nat Med 13(4): 439-47.

Rajan, P., K. I. Park, V. Ourednik, J. P. Lee, J. Imitola, F. J. Müller, Y. D. Teng and E. Y. Snyder (2007). Stem cell research & applications for human therapies. Drug Discovery Research in the Post Genomics Era. Z. Huang. Hoboken, Wiley & Sons.



2006


Müller, F. J., E. Y. Snyder and J. F. Loring (2006). "Gene therapy: can neural stem cells deliver?" Nat Rev Neurosci 7(1): 75-84.

Müller, F. J., N. Serobyan, I. U. Schraufstatter, R. DiScipio, D. Wakeman, J. F. Loring, E. Y. Snyder and S. K. Khaldoyanidi (2006). "Adhesive interactions between human neural stem cells and inflamed human vascular endothelium are mediated by integrins."
Stem Cells 24(11): 2367-72.

Kim, D. E., K. Tsuji, Y. R. Kim, F. J. Müller, H. S. Eom, E. Y. Snyder, E. H. Lo, R. Weissleder and D. Schellingerhout (2006). "Neural stem cell transplant survival in brains of mice: assessing the effect of immunity and ischemia by using real-time bioluminescent imaging."
Radiology 241(3): 822-30.

Liu Y, Shin S, Zeng X, Zhan M, Gonzalez R, Mueller F-J, Schwartz CM, Xue H, Li H, Baker SC, Chudin E, Barker DL, McDaniel TK, Oeser S, Loring JF, Mattson MP, Rao MS. Genome wide profiling of human embryonic stem cells (hESCs), their derivatives and embryonal carcinoma cells to develop base profiles of U.S. Federal government approved hESC lines.
BMC Dev Biol. 2006;6:20.



2005

Müller FJ, Koch JM, Baier PC. Reduced daytime activity in Musca Domestica after sleept deprivation by gently handling them an instruction manual. Sperling N, editor. The Journal of Irreproducible Results. 2005 Sep 1;49(5):25–7.

Müller, FJ, S. R. McKercher, J. Imitola, J. F. Loring, S. Yip, S. J. Khoury and E. Y. Snyder (2005). "At the interface of the immune system and the nervous system: how neuroinflammation modulates the fate of neural progenitors in vivo." Ernst Schering Res Found Workshop(53): 83-114.



2004


Imitola, J., K. I. Park, Y. D. Teng, S. Nisim, M. Lachyankar, J. Ourednik, F. J. Müller, R. Yiou, A. Atala, R. L. Sidman, M. Tuszynski, S. J. Khoury and E. Y. Snyder (2004). "Stem cells: cross-talk and developmental programs." Philos Trans R Soc Lond B Biol Sci 359(1445): 823-37.

Imitola, J., K. Raddassi, K. I. Park, F. J. Müller, M. Nieto, Y. D. Teng, D. Frenkel, J. Li, R. L. Sidman, C. A. Walsh, E. Y. Snyder and S. J. Khoury (2004). "Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway."
Proc Natl Acad Sci U S A 101(52): 18117-22.