iPSCs for Disease Modelling, Drug Screening and Cell Therapy

Objectives

Research of the Clinic of Cardiothoracic, Transplantation and Vascular surgery is dedicated to clinically relevant topics of organ transplantation, the development of functionalized implants and regenerative medicine. In the Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO) different aspects of regenerative medicine and organ transplantation are investigated.

Research Focus

Technologies for generation of clinically relevant patient-specific induced pluripotent stem cells (iPSCs) together with exciting new tools for highly efficient targeted genome engineering create new options for basic research, disease modelling, drug screening and therapeutic application of iPSC derivatives, and are therefore in the focus of this research group.

These technologies include TALE nuclease (TALEN) and CRISPR/Cas-based genome editing, which is applied to efficiently introduce transgenes or mutations into specific genomic loci, to correct disease-specific mutations in patient-derived iPSCs or to knock out single genes or even larger parts of the genome.

Using these techniques, reporter cell lines are generated in order to screen for therapeutically relevant compounds, and specific mutations are tested for their disease phenotype (collaboration with REBIRTH Unit 4.2).

Also, the ability to efficiently introduce transgenes at specific safe genomic loci represents a straightforward approach for the generation of clinically applicable transgenic pluripotent stem cell lines and enables the parallel expression of several transgenes with defined expression levels. In case of genetic defects of patient-derived iPSCs, cells need to be corrected before they can be re-transplanted into the patient. Additionally, the safety of clinical use of pluripotent stem cell lines is addressed, e.g., by introducing an inducible caspase-9 safety switch like the iCasp9 cell-suicide system. Another application is to engineer the human HLA system for development of non-alloreactive universal cell lines.

A further focus of the group is the investigation of potential risks during therapeutic applications of iPSC derivatives, especially mutations in the nuclear and mitochondrial genomes that may be inherited from source cells or arise during reprogramming and expansion. In this context, we are also interested to compare the “biological quality” of iPSCs from old versus young cell sources. Moreover, we are analyzing the role of human non-LTR retrotransposons (LINE-1 elements) which might induce genetic aberrations and may alter gene expression.

Noteworthy, preclinical large animal studies are required to assess safety and efficacy of iPSC-based cellular therapies. Among the large animal species frequently used in preclinical efficacy and safety studies, pigs and sheep are of special importance. However, macaques show the highest similarities to humans at physiological, cellular, and molecular levels and thus iPSCs from Cynomolgus monkeys (cyiPSCs) have been generated and, besides human cells, may be applied in preclinical large animal models. In collaboration with the German Primate Center and further national partners, preclinical in vivo studies are conducted that apply hiPSCs for heart repair in a non-human primate model of myocardial infarction. Moreover, in close collaboration with the GMP development unit at MHH, we are developing GMP-compliant protocols and SOPs for generation and gene editing of clinically applicable hiPSCs.

Genetically engineered disease specific iPSCs for disease modelling, drug screening and toxicity testing

Achievements/Planning

In view of future clinical application, we conducted a comprehensive study to investigate in detail the type, frequency and origin of genetic abnormalities in human iPSCs. Importantly we also aimed at answering the question whether iPSCs derived from old individuals harbor more chromosomal abnormalities than iPSCs derived from neonatal cell sources. Karyotype analyses as well as Array CGH were performed in close collaboration with the REBIRTH groups 9.5 and 9.6 (Steinemann, Göhring). For exom sequencing, a new SOLiD 5500 device funded by the BMBF was used and necessary bioinformatics were established in close collaboration with the group of B. Tümmler at MHH.

Disease-specific iPSC lines for modelling cardiomyopathies were established from patients with different mutations. Also several iPSC lines from cystic fibrosis patients with the most common ΔF508 mutation were established. Finally, we successfully generated cyiPSCs from skin fibroblasts, resulting in almost identical growth characteristics as compared to cynomolgus embryonic stem cells. We were also able to differentiate these cells into functional cardiomyocytes and to generate transgenic cyiPSC clones with stable reporter expression to enable cell tracking in recipient animals. Cardiac differentiation of the cyiPSCs is currently optimized together with researchers from Unit 5.7.

Both the Zinc Finger Nuclease (ZFN)- and the TALEN-based approach have already been successfully used in our lab for highly efficient gene engineering (Merkert et al., Stem Cell Reports, 2014) and to correct for genetic defects in patient-derived iPSCs. Moreover, we successfully established a TALEN assembly platform to generate various TALENs for several reporter cell lines for cardiomyocyte and lung-specific differentiation, and further gene correction approaches.

 

 

Collaborations

  • S. Boretius, F.-J. Kaup, German Primate Center, Göttingen (non-human primates, MRT)
  • U. Köhl, L. Arseniev, Institute for Cellular Therapeutics (ICT) (GMP compliant generation, characterization and transgenesis of hiPSCs)
  • A. Braun, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) (histology)
  • N. Hoppe, Centre for Ethics and Law in the Life Sciences (CELLS), Leibniz University Hannover (LUH) (ethical, legal and social issues)
  • S. Knöbel, D. Eckardt, Miltenyi Biotec GmbH (production of TALENs and media for cardiomyocyte production; cardiomyocyte subtype analyses)
  • M. Harder, corlife oHG (development of marketing strategies for stem cell products)
  • M Amaral, University of Lisboa, FCUL-Faculty of Sciences, Portugal (iPSC-based drug screening, CF research)
  • J. Rossant, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Canada (differentiation of human iPSCs towards respiratory epithelial cells, iPSC-based drug screening, CF research)
  • J. W. Hanrahan, McGill University, Department of Physiology, Montreal, Québec Canada (iPSC-based drug screening, CF research)
  • Y. Reisner, Weizmann Institute of Science, Rehovot, Israel (intra venous transplantation of hiPSC derived lung epithelial (progenitor) cells in lung disease mouse model)
  • Evogene Plant Innovation, Rehovot, Israel (iPSC-based drug screening, CF research)
  • E. Curnow, Washington National Primate Research Center (cyiPSCs)
  • L. Galietta, Ospedale Gaslini, Genoa, Italy (iPSC-based drug screening, CF research)
  • G. Göhring, D. Steinemann, Dept. of Mol. Pathol., MHH (Karyotyping, Array CGH)
  • I. Gruh, HTTG, MHH (cardiac differentiation)
  • B. Tümmler, Paed. Pneumology, MHH (exom sequencing)
  • G. Schumann, Paul-Ehrlich-Institut, Langen (LINE-1)
  • B. Scholte, Erasmus MC Rotterdam, Netherlands (iPSC-based drug screening, CF research)
  • R. Schermuly, S. Bellusci, Gießen (iPSCs as in vitro disease model for pulmonary hypertension)
  • BMWZ – Biomolecular Center of Drug Research, LUH: Collaborations with groups of A. Kirschning, O. Plettenburg and G. Dräger (drug screening)
  • DZL: Close collaborations with RGs of M. Ochs, G. Hansen, B. Tümmler, S. Korossis/ B. Wiegmann (iPSC-based drug screening, CF research, iPSC-derived endothelial cells for seeding of extracorporal membrane oxygenators)
  • HTTG clinic, MHH (old somatic cells)
  • NIFE - Lower Saxony Centre for Biomedical Engineering, Implant Research and Development: Collaborations with groups of A. Heisterkamp, A. Kirschning, G. Dräger and T. Scheper (surface coating and seeding of implant surfaces, development of a biohybrid lung etc.)

Public Relations

  • Prof. Martin was acting president of the German Stem Cell Network (GSCN) from 2015-2016 and is currently senior president of the GSCN

Further Research Projects

  • DFG: T. Kraft, B. Brenner, R. Zweigerdt, U. Martin, Project: An in vitro model for Familial Hypertrophic Cardiomyopathy based on cardiomyoctes derived from human induced pluripotent stem cells
  • DFG: numerous PIs from MHH, Project: KFO 311 - (Prä-)terminales Herz- und Lungenversagen: mechanische Entlastung und Reparatur; Subproject: Ex vivo Gentherapie der pulmonalarteriellen Hypertonie mittels therapeutisch funktionalisierter iPS-Zell-abgeleiteter Endothelzellen nach Präkonditionierung im ex-vivo lung perfusion system (EVLP)
  • DFG: numerous project partners from MHH and other institutions, Project: Schwerpunktprogramm “Towards an Implantable Lung“ (SPP 2014/1); Subproject number 16: Patient-specific induced pluripotent stem (iPS) cells for endothelialisation of membrane surfaces of implantable biohybrid lung devices
  • BMBF: numerous PIs from MHH; Coordination ELD: Haverich/ Martin, Project: BREATH - Biomedical Research in Endstage And ObsTructive Lung Disease Hannover; Sub-project ELD-3.1: Generation of iPS-derived endothelial cells (EC) for a biohybrid lung and therapies targeting pulmonary hypertension (PH); Sub-project ELD-3.2: Treatment of Pulmonary Diseases based on Pluripotent Stem Cells ;Flagship project 1: Induced pluripotent stem cells from PAH patients with heterozygous BMPR2 mutations: a search for gene correctors/potentiators and evaluation as a therapeutic approach
  • BMBF: U. Martin, A. Haverich, S. Sarikouch, R. Zweigerdt, I. Gruh, S. Cebotari, HTTG, MHH; U. Köhl, ICT, MHH; S. Boretius, F. J. Kaup, DPZ, Göttingen; A. Braun, ITEM, Hannover; D. Eckardt, S. Knöbel, Miltenyi Biotech GmbH, Bergisch Gladbach; M. Harder, corlife oHG, Hannover; N. Hoppe, CELLS, LUH, Hannover; Project: iCARE - Induced pluripotent stem cells for Clinically Applicable heart Repair; coordinated by U. Martin
  • IMI/EU: numerous project partners, U. Martin, R. Zweigerdt, Project: StemBANCC - Stem cells for Biological Assays of Novel drugs and prediCtive toxicology
  • EU: R. Zweigerdt, A. Haverich, U. Martin (MHH), C. Mummery (LUMC, Netherlands), P. Andrews (USF, UK), G. Pasterkamp (MCU, Netherlands), J. Itskovitz-Eldor (TIT, Israel), D. Strunk, K. Schallmoser (PMU; Austria), K. Kinast, M. Arnold (DASGIP, Germany), P. Mathuis (OVIZIO, Belgium), Project: Tools and Technologies for breakthrough in heart therapies – TECHNOBEAT
  • EU: U. Martin, M. Amaral (FCUL-Faculty of Sciences, University of Lisboa), L. Galietta (Istituto Giannina Gaslini – U.O.C. Genetica Medica), B.J. Scholte (Erasmus MC Rotterdam), J. Rossant (Peter Gilgan Centre for Research and Learning), J.W. Hanrahan (Department of Physiology, McGill University), Project: INSTINCT - Induced pluripotent stem cells for identification of novel drug combinations targeting cystic fibrosis lung and liver disease
  • MWK: numerous PIs, Project: R2N „Replace“ und „Reduce“ aus Niedersachsen; Ersatz- und Ergänzungsmethoden für eine zukunftsweisende biomedizinische Forschung; Subproject B5: Generierung funktioneller Atemwegsepithelzellen aus humanen induzierten pluripotenten Stammzellen als Zellquelle für toxikologische Testsysteme

Publications

2013 - ongoing

2018

Beckmann E*, Kensah G*, Neumann A, Benecke N, Martens A, Martin U, Gruh I and Haverich A. Prolonged Myocardial Protection during Hypothermic Storage: Potential Application for Cardiac Surgery and Myocardial Tissue Engineering. Biomedical Physics and Engineering Express. In Press. *Authors contributed equally.

Harrison PT, Hoppe N and Martin U. Gene editing & stem cells. J Cyst Fibros 17. 2018. no. 1:10.

Iorga B, Schwanke K, Weber N, Wendland M, Greten S, Piep B, dos Remedios CG, Martin U, Zweigerdt R, Kraft T and Brenner B. Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms. Frontiers in Physiology 8. 2018. no. 1111.

Merkert S and Martin U. Targeted Gene Editing in Human Pluripotent Stem Cells Using Site-Specific Nucleases. Adv Biochem Eng Biotechnol. 2018. 163:169.

Neehus AL*, Lam J*, Haake K, Merkert S, Schmidt N, Mucci A, Ackermann M, Schubert M, Happle C, Kuhnel MP, Blank P, Philipp F, Goethe R, Jonigk D, Martin U, Kalinke U, Baumann U, Schambach A, Roesler J and Lachmann N. Impaired IFNgamma-Signaling and Mycobacterial Clearance in IFNgammaR1-Deficient Human iPSC-Derived Macrophages. Stem Cell Reports 10. 2018. no. 1:7. *Authors contributed equally.

Olmer R*, Engels L*, Usman A, Menke S, Malik MNH, Pessler F, Goehring G, Bornhorst D, Bolten S, Abdelilah-Seyfried S, Scheper T, Kempf H, Zweigerdt R and Martin U. Differentiation of human pluripotent stem cells into functional endothelial cells in scalable suspension culture. Stem Cell Reports. In Press. *Authors contributed equally.

Pamies D, Bal-Price A , Chesné C, Coecke S, Dinnyes A, Eskes C, Grillari R, Gstraunthaler G, Hartung T, Jennings P, Leist M, Martin U, Passier R, Schwamborn JC, Stacey GN, Ellinger-Ziegelbauer H and Daneshian M. Advanced Good Cell Culture Practice for human primary, stem cell-derived and organoid models as well as microphysiological systems. ALTEX. In Press.

Weist R, Flörkemeier T, Roger Y, Franke A, Schwanke K, Zweigerdt R, Martin U, Willbold E# and Hoffmann A#. Differential expression of cholinergic system components in human induced pluripotent stem cells, bone marrow‐derived multipotent stromal cells, and induced pluripotent stem cell-derived multipotent stromal cells. Stem Cells and Development 27. 2018. no. 3:166. #Authors contributed equally.

2017

Merkert S, Bednarski C, Gohring G, Cathomen T, Martin U. Generation of a gene-corrected isogenic control iPSC line from cystic fibrosis patient-specific iPSCs homozygous for p.Phe508del mutation mediated by TALENs and ssODN. Stem Cell Res. 2017/09/20 ed2017. p. 95-7.

Martin U. Genome stability of programmed stem cell products. Adv Drug Deliv Rev. 2017/09/18 ed2017. p. 108-17.

Haase A, Gohring G, Martin U. Generation of non-transgenic iPS cells from human cord blood CD34(+) cells under animal component-free conditions. Stem Cell Res. 2017/07/06 ed2017. p. 71-3.

Massai D, Bolesani E, Diaz DR, Kropp C, Kempf H, Halloin C, Martin U, Braniste T, Isu G, Harms V, Morbiducci U, Drager G, Zweigerdt R. Sensitivity of human pluripotent stem cells to insulin precipitation induced by peristaltic pump-based medium circulation: considerations on process development. Sci Rep. 2017/06/24 ed2017. p. 3950.

Ackermann M*, Kuhn A*, Kunkiel J, Merkert S, Martin U, Moritz T, Lachmann N. Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells. Transfus Med Hemother. 2017/06/20 ed2017. p. 135-42. *Authors contributed equally.

Rojas SV, Kensah G, Rotaermel A, Baraki H, Kutschka I, Zweigerdt R, Martin U, Haverich A, Gruh I#, Martens A#. Transplantation of purified iPSC-derived cardiomyocytes in myocardial infarction. PLoS One. 2017/05/12 ed2017. p. e0173222. #Authors contributed equally.

Rojas SV, Meier M, Zweigerdt R, Eckardt D, Rathert C, Schecker N, Schmitto JD, Rojas-Hernandez S, Martin U, Kutschka I, Haverich A, Martens A. Multimodal Imaging for In Vivo Evaluation of Induced Pluripotent Stem Cells in a Murine Model of Heart Failure. Artificial organs. 2017;41(2):192-9.

Jara-Avaca M*, Kempf H*, Ruckert M, Robles-Diaz D, Franke A, de la Roche J, Fischer M, Malan D, Sasse P, Solodenko W, Drager G, Kirschning A, Martin U#, Zweigerdt R#. EBIO Does Not Induce Cardiomyogenesis in Human Pluripotent Stem Cells but Modulates Cardiac Subtype Enrichment by Lineage-Selective Survival. Stem cell reports. 2017. *#Authors contributed equally.

Martin U. Therapeutic Application of Pluripotent Stem Cells: Challenges and Risks. Front Med. 2017. 4:229.

Martin U and Haverich A. Myocardial tissue engineering. From basic research to clinical application. Zeitschrift für Herz-, Thorax- und Gefäßchirurgie 31. 2017. no. 3:200.

Stanslowsky N, Jahn K, Venneri A, Naujock M, Haase A, Martin U, Frieling H and Wegner F. Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells. Addict Biol 22. 2017. no. 5:1329.

 

2016

Weber N, Schwanke K, Greten S, Wendland M, Iorga B, Fischer M, Geers-Knorr C, Hegermann J, Wrede C, Fiedler J, Kempf H, Franke A, Piep B, Pfanne A, Thum T, Martin U, Brenner B, Zweigerdt R, Kraft T. Stiff matrix induces switch to pure beta-cardiac myosin heavy chain expression in human ESC-derived cardiomyocytes. Basic research in cardiology. 2016;111(6):68.

Stanslowsky N, Jahn K, Venneri A, Naujock M, Haase A, Martin U, Frieling H, Wegner F. Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells. Addiction biology. 2016.

Merkert S, Martin U. Targeted genome engineering using designer nucleases: State of the art and practical guidance for application in human pluripotent stem cells. Stem cell research. 2016;16(2):377-86.

Merkert S, Martin U. Site-Specific Genome Engineering in Human Pluripotent Stem Cells. International journal of molecular sciences. 2016;17(7).

Kropp C, Kempf H, Halloin C, Robles-Diaz D, Franke A, Scheper T, Kinast K, Knorpp T, Joos TO, Haverich A, Martin U, Zweigerdt R, Olmer R. Impact of Feeding Strategies on the Scalable Expansion of Human Pluripotent Stem Cells in Single-Use Stirred Tank Bioreactors. Stem cells translational medicine. 2016;5(10):1289-301.

Klawitter S, Fuchs NV, Upton KR, Munoz-Lopez M, Shukla R, Wang J, Garcia-Canadas M, Lopez-Ruiz C, Gerhardt DJ, Sebe A, Grabundzija I, Merkert S, Gerdes P, Pulgarin JA, Bock A, Held U, Witthuhn A, Haase A, Sarkadi B, Lower J, Wolvetang EJ, Martin U, Ivics Z, Izsvak Z, Garcia-Perez JL, Faulkner GJ, Schumann GG. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nature communications. 2016;7:10286.

Kempf H, Olmer R, Haase A, Franke A, Bolesani E, Schwanke K, Robles-Diaz D, Coffee M, Gohring G, Drager G, Potz O, Joos T, Martinez-Hackert E, Haverich A, Buettner FF, Martin U, Zweigerdt R. Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells. Nature communications. 2016;7:13602.

Borger AK, Eicke D, Wolf C, Gras C, Aufderbeck S, Schulze K, Engels L, Eiz-Vesper B, Schambach A, Guzman CA, Lachmann N, Moritz T, Martin U, Blasczyk R, Figueiredo C. Generation of HLA-universal iPSCs-derived megakaryocytes and platelets for survival under refractoriness conditions. Molecular medicine. 2016;22.

Beckmann A, Schubert M, Hainz N, Haase A, Martin U, Tschernig T, Meier C. Ultrastructural demonstration of Cx43 gap junctions in induced pluripotent stem cells from human cord blood. Histochemistry and cell biology. 2016;146(5):529-37.

2015

Martin U. Pluripotent stem cells for disease modeling and drug screening: new perspectives for treatment of cystic fibrosis? Molecular and cellular pediatrics. 2015;2(1):15.

Effenberg A, Stanslowsky N, Klein A, Wesemann M, Haase A, Martin U, Dengler R, Grothe C, Ratzka A, Wegner F. Striatal Transplantation of Human Dopaminergic Neurons Differentiated From Induced Pluripotent Stem Cells Derived From Umbilical Cord Blood Using Lentiviral Reprogramming. Cell transplantation. 2015;24(10):2099-112.

Rojas SV*, Martens A*, Zweigerdt R, Baraki H, Rathert C, Schecker N, Rojas-Hernandez S, Schwanke K, Martin U, Haverich A, Kutschka I. Transplantation Effectiveness of Induced Pluripotent Stem Cells Is Improved by a Fibrinogen Biomatrix in an Experimental Model of Ischemic Heart Failure. Tissue Eng Part A. 2015;21(13-14):1991-2000. Epub 2015/04/14.

Martin U. Pluripotent Stem Cells for Disease Modeling and Drug Screening: New Perspectives for Treatment of Cystic Fibrosis? Mol Cell Pediatr. 2015;2(1):15.

Martin U. New Muscle for Old Hearts: Engineering Tissue from Pluripotent Stem Cells. Hum Gene Ther. 2015;26(5):305-11.

Kempf H*, Kropp C*, Olmer R, Martin U, Zweigerdt R. Cardiac Differentiation of Human Pluripotent Stem Cells in Scalable Suspension Culture. Nat Protoc. 2015;10(9):1345-61.

Katsirntaki K, Mauritz C, Olmer R, Schmeckebier S, Sgodda M, Puppe V, Eggenschwiler R, Duerr J, Schubert SC, Schmiedl A, Ochs M, Cantz T, Salwig I, Szibor M, Braun T, Rathert C, Martens A, Mall MA, Martin U. Bronchoalveolar Sublineage Specification of Pluripotent Stem Cells: Effect of Dexamethasone Plus Camp-Elevating Agents and Keratinocyte Growth Factor. Tissue Eng Part A. 2015;21(3-4):669-82.

Effenberg A, Stanslowsky N, Klein A, Wesemann M, Haase A, Martin U, Dengler R, Grothe C, Ratzka A, Wegner F. Striatal Transplantation of Human Dopaminergic Neurons Differentiated from Induced Pluripotent Stem Cells Derived from Umbilical Cord Blood Using Lentiviral Reprogramming. Cell Transplant. 2015;24(10):2099-112.

2014

Zweigerdt R, Gruh I, Martin U. Your Heart on a Chip: Ipsc-Based Modeling of Barth-Syndrome-Associated Cardiomyopathy. Cell Stem Cell. 2014;15(1):9-11.

Wunderlich S, Kircher M, Vieth B, Haase A, Merkert S, Beier J, Gohring G, Glage S, Schambach A, Curnow EC, Paabo S, Martin U, Enard W. Primate Ips Cells as Tools for Evolutionary Analyses. Stem Cell Res. 2014;12(3):622-9.

Stanslowsky N, Haase A, Martin U, Naujock M, Leffler A, Dengler R, Wegner F. Functional Differentiation of Midbrain Neurons from Human Cord Blood-Derived Induced Pluripotent Stem Cells. Stem Cell Res Ther. 2014;5(2):35.

Schwanke K, Merkert S, Kempf H, Hartung S, Jara-Avaca M, Templin C, Gohring G, Haverich A, Martin U, Zweigerdt R. Fast and Efficient Multitransgenic Modification of Human Pluripotent Stem Cells. Hum Gene Ther Methods. 2014;25(2):136-53.

Naujock M, Stanslowsky N, Reinhardt P, Sterneckert J, Haase A, Martin U, Kim KS, Dengler R, Wegner F, Petri S. Molecular and Functional Analyses of Motor Neurons Generated from Human Cord-Blood-Derived Induced Pluripotent Stem Cells. Stem Cells Dev. 2014;23(24):3011-20.

Merkert S, Wunderlich S, Bednarski C, Beier J, Haase A, Dreyer AK, Schwanke K, Meyer J, Gohring G, Cathomen T, Martin U. Efficient Designer Nuclease-Based Homologous Recombination Enables Direct Pcr Screening for Footprintless Targeted Human Pluripotent Stem Cells. Stem Cell Reports. 2014;2(1):107-18.

Martin U, Haverich A. Engineering Cardiac Muscle: New Ways to Refurbish Old Hearts? Eur J Cardiothorac Surg. 2014;45(2):216-9.

Martens A*, Rojas SV*, Baraki H, Rathert C, Schecker N, Zweigerdt R, Schwanke K, Rojas-Hernandez S, Martin U, Saito S, Schmitto JD, Haverich A, Kutschka I. Substantial Early Loss of Induced Pluripotent Stem Cells Following Transplantation in Myocardial Infarction. Artif Organs. 2014;38(11):978-84.

Martens A*, Rojas SV*, Baraki H, Rathert C, Schecker N, Hernandez SR, Schwanke K, Zweigerdt R, Martin U, Saito S, Haverich A, Kutschka I. Macroscopic Fluorescence Imaging: A Novel Technique to Monitor Retention and Distribution of Injected Microspheres in an Experimental Model of Ischemic Heart Failure. PLoS One. 2014;9(8):e101775.

Lachmann N, Happle C, Ackermann M, Luttge D, Wetzke M, Merkert S, Hetzel M, Kensah G, Jara-Avaca M, Mucci A, Skuljec J, Dittrich AM, Pfaff N, Brennig S, Schambach A, Steinemann D, Gohring G, Cantz T, Martin U, Schwerk N, Hansen G, Moritz T. Gene Correction of Human Induced Pluripotent Stem Cells Repairs the Cellular Phenotype in Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2014;189(2):167-82.

Kempf H, Olmer R, Kropp C, Ruckert M, Jara-Avaca M, Robles-Diaz D, Franke A, Elliott DA, Wojciechowski D, Fischer M, Roa Lara A, Kensah G, Gruh I, Haverich A, Martin U, Zweigerdt R. Controlling Expansion and Cardiomyogenic Differentiation of Human Pluripotent Stem Cells in Scalable Suspension Culture. Stem Cell Reports. 2014;3(6):1132-46.

2013

Schmeckebier S, Mauritz C, Katsirntaki K, Sgodda M, Puppe V, Duerr J, Schubert SC, Schmiedl A, Lin Q, Palecek J, Draeger G, Ochs M, Zenke M, Cantz T, Mall MA, Martin U. Keratinocyte Growth Factor and Dexamethasone Plus Elevated Camp Levels Synergistically Support Pluripotent Stem Cell Differentiation into Alveolar Epithelial Type Ii Cells. Tissue Eng Part A. 2013;19(7-8):938-51.

Kues WA, Herrmann D, Barg-Kues B, Haridoss S, Nowak-Imialek M, Buchholz T, Streeck M, Grebe A, Grabundzija I, Merkert S, Martin U, Hall VJ, Rasmussen MA, Ivics Z, Hyttel P, Niemann H. Derivation and Characterization of Sleeping Beauty Transposon-Mediated Porcine Induced Pluripotent Stem Cells. Stem Cells Dev. 2013;22(1):124-35.

Kensah G, Roa Lara A, Dahlmann J, Zweigerdt R, Schwanke K, Hegermann J, Skvorc D, Gawol A, Azizian A, Wagner S, Maier LS, Krause A, Drager G, Ochs M, Haverich A, Gruh I, Martin U. Murine and Human Pluripotent Stem Cell-Derived Cardiac Bodies Form Contractile Myocardial Tissue in Vitro. Eur Heart J. 2013;34(15):1134-46.

Hartung S, Schwanke K, Haase A, David R, Franz WM, Martin U, Zweigerdt R. Directing Cardiomyogenic Differentiation of Human Pluripotent Stem Cells by Plasmid-Based Transient Overexpression of Cardiac Transcription Factors. Stem Cells Dev. 2013;22(7):1112-25.

Emmert MY, Emmert LS, Martens A, Ismail I, Schmidt-Richter I, Gawol A, Seifert B, Haverich A, Martin U, Gruh I. Higher Frequencies of Bcrp+ Cardiac Resident Cells in Ischaemic Human Myocardium. Eur Heart J. 2013;34(36):2830-8.

Dahlmann J, Krause A, Moller L, Kensah G, Mowes M, Diekmann A, Martin U, Kirschning A, Gruh I, Drager G. Fully Defined in Situ Cross-Linkable Alginate and Hyaluronic Acid Hydrogels for Myocardial Tissue Engineering. Biomaterials. 2013;34(4):940-51.

Dahlmann J, Kensah G, Kempf H, Skvorc D, Gawol A, Elliott DA, Dräger G, Zweigerdt R, Martin U, Gruh I. The Use of Agarose Microwells for Scalable Embryoid Body Formation and Cardiac Differentiation of Human and Murine Pluripotent Stem Cells. Biomaterials. 2013;34(10):2463-71.

Buta C, David R, Dressel R, Emgard M, Fuchs C, Gross U, Healy L, Hescheler J, Kolar R, Martin U, Mikkers H, Muller FJ, Schneider RK, Seiler AE, Spielmann H, Weitzer G. Reconsidering Pluripotency Tests: Do We Still Need Teratoma Assays? Stem Cell Res. 2013;11(1):552-62. Epub 2013/04/25.

2006 - 2012

2012

Templin C, Martin U. Nichtinvasiver Nachweis transplantierter iPSCs. Laborwelt. 2012;4:22

Martin U. Induced Pluripotent Stem Cells from Blood. In: Regenerative Therapy Using Blood-Derived Stem Cells. Allan DS, Strunk D, editors. Humana Press; 2012. p. 87-95. 14. Springer-Verlag, ISBN 978-1-61779-470-4.

Wunderlich S, Haase A, Merkert S, Beier J, Schwanke K, Schambach A, Glage S, Gohring G, Curnow EC, Martin U. Induction of Pluripotent Stem Cells from a Cynomolgus Monkey Using a Polycistronic Simian Immunodeficiency Virus-Based Vector, Differentiation toward Functional Cardiomyocytes, and Generation of Stably Expressing Reporter Lines. Cell Reprogram. 2012;14(6):471-84.

Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri JR, Emmert MY, Muller E, Kuest SM, Cohrs S, Schibli R, Kronen P, Hilbe M, Reinisch A, Strunk D, Haverich A, Hoerstrup S, Luscher TF, Kaufmann PA, Landmesser U, Martin U. Transplantation and Tracking of Human-Induced Pluripotent Stem Cells in a Pig Model of Myocardial Infarction: Assessment of Cell Survival, Engraftment, and Distribution by Hybrid Single Photon Emission Computed Tomography/Computed Tomography of Sodium Iodide Symporter Transgene Expression. Circulation. 2012;126(4):430-9.

Olmer R, Lange A, Selzer S, Kasper C, Haverich A, Martin U, Zweigerdt R. Suspension Culture of Human Pluripotent Stem Cells in Controlled, Stirred Bioreactors. Tissue Eng Part C Methods. 2012;18(10):772-84.

Fiechter M, Ghadri JR, Sidler M, Martin U, Landmesser U, Kaufmann PA, Luscher TF, Templin C. Cardiac Quadruple-Fusion Imaging: A Brief Report on a Novel Integrated Multimodality Approach for in Vivo Visualization of Transplanted Stem Cells. Int J Cardiol. 2012;161(1):62-3.

Chen R, John J, Lavrentieva A, Müller S, Tomala M, Zhao Y, Zweigerdt R, Beutel S, Hitzmann B, Kasper C, Martin U, Rinas U, Stahl F, Scheper T. Cytokine Production Using Membrane Adsorbers: Human Basic Fibroblast Growth Factor Produced by Escherichia Coli. Engineering in Life Sciences. 2012;12(1):29-38.

2011

Grolms M, Olmer R, Martin U, Zweigerdt R. Facilitating scale up:controlled stem cell cultivation in stirred suspension bioreactors. Biotech International 19. 2011 (www.biotech-online.com & search 12630).

Zweigerdt R, Olmer R, Singh H, Haverich A, Martin U. Scalable Expansion of Human Pluripotent Stem Cells in Suspension Culture. Nat Protoc. 2011;6(5):689-700.

Palecek J, Zweigerdt R, Olmer R, Martin U, Kirschning A, Drager G. A Practical Synthesis of Rho-Kinase Inhibitor Y-27632 and Fluoro Derivatives and Their Evaluation in Human Pluripotent Stem Cells. Org Biomol Chem. 2011;9(15):5503-10.

Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A, Martin U, Kutschka I. Induced Pluripotent Stem Cell (Ipsc)-Derived Flk-1 Progenitor Cells Engraft, Differentiate, and Improve Heart Function in a Mouse Model of Acute Myocardial Infarction. Eur Heart J. 2011;32(21):2634-41.

Martens A, Gruh I, Dimitroulis D, Rojas SV, Schmidt-Richter I, Rathert C, Khaladj N, Gawol A, Chikobava MG, Martin U, Haverich A, Kutschka I. Rhesus Monkey Cardiosphere-Derived Cells for Myocardial Restoration. Cytotherapy. 2011;13(7):864-72.

Kuetemeyer K, Kensah G, Heidrich M, Meyer H, Martin U, Gruh I, Heisterkamp A. Two-Photon Induced Collagen Cross-Linking in Bioartificial Cardiac Tissue. Opt Express. 2011;19(17):15996-6007.

Kensah G, Gruh I, Viering J, Schumann H, Dahlmann J, Meyer H, Skvorc D, Bar A, Akhyari P, Heisterkamp A, Haverich A, Martin U. A Novel Miniaturized Multimodal Bioreactor for Continuous in Situ Assessment of Bioartificial Cardiac Tissue During Stimulation and Maturation. Tissue Eng Part C Methods. 2011;17(4):463-73.

Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JT, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J, Thum T. Microrna-24 Regulates Vascularity after Myocardial Infarction. Circulation. 2011;124(6):720-30.

2010

Mauritz C, Martin U. Embryonic Stem Cells: Differentiation into Respiratory Cell Derivatives. In Stem cells: organogenesis and cancer. Vol. 37/661 (2). S.R. Singh, editor. Transworld Research Networ. 2010. ISBN 978-81-7895-487-5.

Ozkan J, Martin U. "In Vitro Generation of Large Blood Vessels Is the Key Technology for the Generation and Implantation of Larger Dimension Tissue". Circulation. 2010;121(13):F76-F8.

Tomala M, Lavrentieva A, Moretti P, Rinas U, Kasper C, Stahl F, Schambach A, Warlich E, Martin U, Cantz T, Scheper T. Preparation of Bioactive Soluble Human Leukemia Inhibitory Factor from Recombinant Escherichia Coli Using Thioredoxin as Fusion Partner. Protein Expr Purif. 2010;73(1):51-7.

Olmer R, Haase A, Merkert S, Cui W, Palecek J, Ran C, Kirschning A, Scheper T, Glage S, Miller K, Curnow EC, Hayes ES, Martin U. Long Term Expansion of Undifferentiated Human Ips and Es Cells in Suspension Culture Using a Defined Medium. Stem Cell Res. 2010;5(1):51-64.

Hess C, Wiegmann B, Maurer AN, Fischer P, Moller L, Martin U, Hilfiker A, Haverich A, Fischer S. Reduced Thrombocyte Adhesion to Endothelialized Poly 4-Methyl-1-Pentene Gas Exchange Membranes-a First Step toward Bioartificial Lung Development. Tissue Eng Part A. 2010;16(10):3043-53.

Cantz T, Martin U. Induced Pluripotent Stem Cells: Characteristics and Perspectives. Adv Biochem Eng Biotechnol. 2010;123:107-26.

2009

Xaymardan M, Cimini M, Fazel S, Weisel RD, Lu WY, Martin U, Harvey RP, Li RK. C-Kit Function Is Necessary for in Vitro Myogenic Differentiation of Bone Marrow Hematopoietic Cells. Stem Cells. 2009;27(8):1911-20. Epub 2009/06/23.

Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C, Zweigerdt R, Gruh I, Meyer J, Wagner S, Maier LS, Han DW, Glage S, Miller K, Fischer P, Scholer HR, Martin U. Generation of Induced Pluripotent Stem Cells from Human Cord Blood. Cell Stem Cell. 2009;5(4):434-41.

Gruh I, Martin U. Transdifferentiation of Stem Cells: A Critical View. Adv Biochem Eng Biotechnol. 2009;114:73-106.

Ghodsizad A, Niehaus M, Kogler G, Martin U, Wernet P, Bara C, Khaladj N, Loos A, Makoui M, Thiele J, Mengel M, Karck M, Klein HM, Haverich A, Ruhparwar A. Transplanted Human Cord Blood-Derived Unrestricted Somatic Stem Cells Improve Left-Ventricular Function and Prevent Left-Ventricular Dilation and Scar Formation after Acute Myocardial Infarction. Heart. 2009;95(1):27-35.

2008

Martin U. Pluripotent Nonhuman Primate Stem Cells for Biomedical Research, Development of Regenerative Therapies and Drug Screening. In Critical Contributions of Primate Models for Biopharmaceutical Drug Development. G. Weinbauer, editor. Waxmann, Münster. 2008.

Wunderlich S, Gruh I, Winkler ME, Beier J, Radtke K, Schmiedl A, Groos S, Haverich A, Martin U. Type Ii Pneumocyte-Restricted Green Fluorescent Protein Expression after Lentiviral Transduction of Lung Epithelial Cells. Hum Gene Ther. 2008;19(1):39-52.

Winkler ME, Mauritz C, Groos S, Kispert A, Menke S, Hoffmann A, Gruh I, Schwanke K, Haverich A, Martin U. Serum-Free Differentiation of Murine Embryonic Stem Cells into Alveolar Type Ii Epithelial Cells. Cloning Stem Cells. 2008;10(1):49-64.

Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS, Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U. Generation of Functional Murine Cardiac Myocytes from Induced Pluripotent Stem Cells. Circulation. 2008;118(5):507-17.

Martin U. Methods for Studying Stem Cells: Adult Stem Cells for Lung Repair. Methods. 2008;45(2):121-32. 

Gruh I, Wunderlich S, Winkler M, Schwanke K, Heinke J, Blomer U, Ruhparwar A, Rohde B, Li RK, Haverich A, Martin U. Human Cmv Immediate-Early Enhancer: A Useful Tool to Enhance Cell-Type-Specific Expression from Lentiviral Vectors. J Gene Med. 2008;10(1):21-32.

2007

Ruhparwar A, Er F, Martin U, Radke K, Gruh I, Niehaus M, Karck M, Haverich A, Hoppe UC. Enrichment of Cardiac Pacemaker-Like Cells: Neuregulin-1 and Cyclic Amp Increase I(F)-Current Density and Connexin 40 Mrna Levels in Fetal Cardiomyocytes. Med Biol Eng Comput. 2007;45(2):221-7.

2006

Schwarzer M, Carnwath JW, Lucas-Hahn A, Lemme E, Kues WA, Wachsmann B, Haverich A, Martin U, Niemann H. Isolation of Bovine Cardiomyocytes for Reprogramming Studies Based on Nuclear Transfer. Cloning Stem Cells. 2006;8(3):150-8.

Schwanke K, Wunderlich S, Reppel M, Winkler ME, Matzkies M, Groos S, Itskovitz-Eldor J, Simon AR, Hescheler J, Haverich A, Martin U. Generation and Characterization of Functional Cardiomyocytes from Rhesus Monkey Embryonic Stem Cells. Stem Cells. 2006;24(6):1423-32.

Ruhparwar A, Ghodsizad A, Niehaus M, Bara C, Lotz J, Voelkel T, Makoui M, Martin U, Wolf F, Gams E, Klein M, Haverich A. Clinically Applicable 7-Tesla Magnetic Resonance Visualization of Transplanted Human Adult Stem Cells Labeled with Clinimacs Nanoparticles. Thorac Cardiovasc Surg. 2006;54(7):447-51.

Ruhparwar A, Bara C, Kofidis T, Ruebesamen N, Karck M, Martin U, Haverich A. [in Vivo Detection of Integration of Grafted Cells after Myocardial Transplantation]. Zentralbl Chir. 2006;131(5):420-4. Bildgebende Verfahren zum In-vivo-Nachweis der Integration transplantierter Zellen im Myokard.

Li Y, Koster T, Morike C, v Horsten S, Martin U, Bader M, Haverich A, Simon AR. Pravastatin Prolongs Graft Survival in an Allogeneic Rat Model of Orthotopic Single Lung Transplantation. Eur J Cardiothorac Surg. 2006;30(3):515-24.

Horn PA, Tani K, Martin U, Niemann H. Nonhuman Primates: Embryonic Stem Cells and Transgenesis. Cloning Stem Cells. 2006;8(3):124-9.

Gruh I, Beilner J, Blomer U, Schmiedl A, Schmidt-Richter I, Kruse ML, Haverich A, Martin U. No Evidence of Transdifferentiation of Human Endothelial Progenitor Cells into Cardiomyocytes after Coculture with Neonatal Rat Cardiomyocytes. Circulation. 2006;113(10):1326-34.

Donath S, Li P, Willenbockel C, Al-Saadi N, Gross V, Willnow T, Bader M, Martin U, Bauersachs J, Wollert KC, Dietz R, von Harsdorf R. Apoptosis Repressor with Caspase Recruitment Domain Is Required for Cardioprotection in Response to Biomechanical and Ischemic Stress. Circulation. 2006;113(9):1203-12. Epub 2006/03/01.

Bara C, Ghodsizad A, Niehaus M, Makoui M, Piechaczek C, Martin U, Warnecke G, Karck M, Gams E, Klein HM, Haverich A, Ruhparwar A. In Vivo Echocardiographic Imaging of Transplanted Human Adult Stem Cells in the Myocardium Labeled with Clinically Applicable Clinimacs Nanoparticles. J Am Soc Echocardiogr. 2006;19(5):563-8.

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