Rational Cell Engineering

Objectives

A promising strategy for regenerative approaches concerns the ex vivo modification of cells that enable themselves (or the recipients) to regain missing functional properties but also to equip cells with novel beneficial functions. Utilizing tools of synthetic biology, we genetically modify cells to render them susceptible towards external and/or physiological signals and to convert these signals into novel biological functions. The vision of this project is to install synthetic devices in cells to develop intelligent, tunable and/or self-controlled cell based therapeutic tools for regenerative approaches.

Reseach Focus

Synthetic regulatory circuits and epigenetic control

We utilize synthetic regulation circuits to express novel functions and to modulate and interfere with cellular pathways in a highly predictable manner. To this end, we employ orthogonal synthetic expression cassettes that respond to external triggers but do not interfere per se with the cellular regulatory network (e.g. by using small molecules). Alternatively, circuits are designed that respond to physiological signals and rewire them to synthetic cassettes. To achieve high predictability, we integrate these cassettes into defined chromosomal loci of stem cells, differentiated cells and mice, employing methods for targeted integration (RMCE, CRISPR/Cas9 based). Particular focus is being laid on the control of crosstalk of the synthetic cassettes with the chromosomal environment, i.e. their site specific epigenetic modulation. This includes the site-specific demethylation of synthetic cassettes to restore transgene expression and avoid silencing (Gödecke et al., 2017). This is being followed in stem cells (Kunkiel et al., 2017; Gödecke et al., 2017), primary cells including macrophages, cell lines (Rand et al., 2014; Rand et al, 2015) as well as transgenic mice (Haenebalcke et al., 2013; Gödecke et al., 2017).

Personalized and proliferation controlled, authentic cell lines

One focus is the establishment of strategies for in vitro expansion of patient specific (personalized) cells without compromising their properties. We developed a novel method to immortalize cells while preserving their functional characteristics (Lipps et al ., 2018). By utilizing externally controlled synthetic devices to control the proliferation status of cells we established physiologically relevant cell lines of various primary cell types that provide controlled proliferation. We showed that in human endothelial cells specific cellular functions are restricted to non-proliferating cells and are downregulated in proliferating cells (Lipps et al., 2017). We currently exploit the plasticity of in vitro expanded cells to establish 3D culture models (single cell types as well as mixed cell types) that mimic the state of the cells in the natural environment in vivo (Lipps et al., 2017). An important objective of this activity is the exploitation of the physiologically relevant 2D and 3D culture models in translational projects such as drug screening and validation as well as for the development of humanized models for diseases (Lipps et al., 2017; Dubich et al., submitted).

Liver regeneration upon immune induced inflammation

Based on a transgenic mouse model for inducible antigen expression we developed a model for CD8 T cell induced hepatitis. With this model, we investigate liver regeneration in sterile conditions, i.e. in absence of secondary signals associated to infection (Cebula et al., 2013). We could demonstrate that a high antigen load in liver blocks immune based clearance of hepatic antigen load, both upon adoptive transfer of specific T cells (Ochel et al., 2016) as well as in context of vaccination (Cebula et al., 2017). Specific modulation of the liver environment facilitated the restoration of potent T cell responses, eventually resulting in complete antigen clearance (Cebula et al., 2017).

Collaborations

  • Dr. Robert Zweigerdt, REBIRTH-Unit 10.2 Mass production of pluripotent stem cells and derivatives.
  • Dr. Nico Lachmann, REBIRTH-Unit 6.8 Translational hematology of congenital diseases
  • Prof. Dr. T. Moritz, Hannover Medical School, REBIRTH-Unit 1.3 iPSC based Haematopoietic Regeneration
  • Prof. Dr. M. Ott, Hannover Medical School, REBIRTH-Unit 3.5 Hepatic Cell Transplantation and Genetic Manipulation
  • Dr. M. Bock, Hannover Medical School, REBIRTH-Unit 3.4 Hepatic Cell Therapy - Patient Liver Stem Cells
  • Prof Dr. A. Schambach, Hannover Medical School, REBIRTH-Unit 6.2 Regenerative Gene Therapy
  • Prof. Dr. T. Cantz, Hannover Medical School, REBIRTH-Unit 1.1 Translational Hepatology and Stem Cell Biology
  • Prof. Dr. Th. Scheper, Leibniz Universität Hannover, REBIRTH-Unit 10.1 Production and Purification of Recombinant Proteins
  • Prof. Dr. Meike Stiesch, Hannover Medical School
  • Prof. Dr. Thomas Schulz, Hannover Medical School

Further Research Projects

  • e:Bio (BMBF): CellSys: Cell line development by synthetic biology
  • DFG: Sensor/effector systems for implant induced inflammation

Teaching

  • Lecturer in the PhD programmes ‚Regenerative Sciences’, Infection Biology’, HZI graduate school
  • Co-supervisor of various PhD students at MHH and HZI Brauschweig

Publications

2013 - ongoing

2018

Lipps C, Klein F, Wahlicht T, Seiffert V, Butueva M, Zauers J, Truschel T, Luckner M, Köster M, MacLeod R, Pezoldt J, Hühn J, Yuan Q, Müller PP, Kempf H, Zweigerdt R, Dittrich-Breiholz O, Pufe T, Beckmann R, Drescher W, Riancho J, Sañudo C, Korff T, Opalka B, Rebmann V, Göthert JR, Alves PM, Ott M, Schucht R, Hauser H, Wirth D, May T. Expansion of functional personalized cells with specific transgene combinations. Nature Communications. 2018;9(1):994.

2017

Lipps C, Badar M, Butueva M, Dubich T, Singh VV, Rau S, Weber A, Kracht M, Köster M, May T, Schulz TF, Hauser H, Wirth D. Proliferation status defines functional properties of endothelial cells. Cellular and Molecular Life Sciences. 2017;74(7):1319-33.

Selvakumar TA, Bhushal S, Kalinke U, Wirth D, Hauser H, Koster M, Hornef MW. Identification of a Predominantly Interferon-lambda-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells. Front Immunol. 2017;8:1302. Epub 2017/11/01.

Riehn M, Cebula M, Hauser H, Wirth D. CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells. Front Immunol. 2017;8:1201. Epub 2017/10/19.

Zhao G, Wirth D, Schmitz I, Meyer-Hermann M. A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. Nat Commun. 2017/11/10 ed2017. p. 1362.

Godecke N, Zha L, Spencer S, Behme S, Riemer P, Rehli M, Hauser H, Wirth D. Controlled re-activation of epigenetically silenced Tet promoter-driven transgene expression by targeted demethylation. Nucleic Acids Res. 2017;45(16):e147. Epub 2017/09/22.

Pasztoi M, Pezoldt J, Beckstette M, Lipps C, Wirth D, Rohde M, Paloczi K, Buzas EI, Huehn J. Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells. Eur J Immunol. 2017;47(12):2142-52. Epub 2017/08/24.

Kunkiel J, Godecke N, Ackermann M, Hoffmann D, Schambach A, Lachmann N, Wirth D, Moritz T. The CpG-sites of the CBX3 ubiquitous chromatin opening element are critical structural determinants for the anti-silencing function. Sci Rep. 2017/08/13 ed2017. p. 7919.

Strandt H, Pinheiro DF, Kaplan DH, Wirth D, Gratz IK, Hammerl P, Thalhamer J, Stoecklinger A. Neoantigen Expression in Steady-State Langerhans Cells Induces CTL Tolerance. J Immunol. 2017;199(5):1626-34. Epub 2017/07/26.

Cebula M, Riehn M, Hillebrand U, Kratzer RF, Kreppel F, Koutsoumpli G, Daemen T, Hauser H, Wirth D. TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. Mol Ther. 2017/07/19 ed2017. p. 2289-98.

Bhushal S, Wolfsmuller M, Selvakumar TA, Kemper L, Wirth D, Hornef MW, Hauser H, Koster M. Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. Front Immunol. 2017;8:671. Epub 2017/07/01.

Pieters T, Haenebalcke L, Bruneel K, Vandamme N, Hochepied T, van Hengel J, Wirth D, Berx G, Haigh JJ, van Roy F, Goossens S. Structure-function Studies in Mouse Embryonic Stem Cells Using Recombinase-mediated Cassette Exchange. J Vis Exp. 2017(122). Epub 2017/05/19.

Gaur P, Cebula M, Riehn M, Hillebrand U, Hauser H, Wirth D. Diet induced obesity has an influence on intrahepatic T cell responses. Metabolism. 2017;69:171-6.

2016

Rais B, Köster M, Rahim Muhammad I, Pils M, Seitz JM, Hauser H, Wirth D, Mueller Peter P. Evaluation of the inflammatory potential of implant materials in a mouse model by bioluminescent imaging of intravenously injected bone marrow cells. Journal of Biomedical Materials Research Part A. 2016;104(9):2149-58.

Tran DD, Koch A, Saran S, Armbrecht M, Ewald F, Koch M, Wahlicht T, Wirth D, Braun A, Nashan B, Gaestel M, Tamura T. Extracellular-signal regulated kinase (Erk1/2), mitogen-activated protein kinase-activated protein kinase 2 (MK2) and tristetraprolin (TTP) comprehensively regulate injury-induced immediate early gene (IEG) response in in vitro liver organ culture. Cellular signalling. 2016;28(5):438-47.

Spencer S, Gugliotta A, Godecke N, Hauser H, Wirth D. Epigenetic modulations rendering cell-to-cell variability and phenotypic metastability. Journal of genetics and genomics = Yi chuan xue bao. 2016;43(8):503-11.

Lipps C, Badar M, Butueva M, Dubich T, Singh VV, Rau S, Weber A, Kracht M, Koster M, May T, Schulz TF, Hauser H, Wirth D. Proliferation status defines functional properties of endothelial cells. Cell Mol Life Sci. 2017;74(7):1319-33. Epub 2016/11/18.

Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. Journal of hepatology. 2016;64(3):556-64.

Kuehn A, Kletting S, de Souza Carvalho-Wodarz C, Repnik U, Griffiths G, Fischer U, Meese E, Huwer H, Wirth D, May T, Schneider-Daum N, Lehr CM. Human alveolar epithelial cells expressing tight junctions to model the air-blood barrier. Altex. 2016;33(3):251-60.

Bachmann M, Breitwieser T, Lipps C, Wirth D, Jordan I, Reichl U, Frensing T. Impaired antiviral response of adenovirus-transformed cell lines supports virus replication. The Journal of general virology. 2016;97(2):293-8.

Ochel A, Cebula M, Riehn M, Hillebrand U, Lipps C, Schirmbeck R, Hauser H, Wirth D. Effective Intrahepatic Cd8+ T-Cell Immune Responses Are Induced by Low but Not High Numbers of Antigen-Expressing Hepatocytes. Cell Mol Immunol. 2015. Epub 2015/09/29

2015

Spencer S, Gugliotta A, Koenitzer J, Hauser H, Wirth D. Stability of Single Copy Transgene Expression in Chok1 Cells Is Affected by Histone Modifications but Not by DNA Methylation. J Biotechnol. 2015;195:15-29. Epub 2014/12/24.

Rand U, Riedel J, Hillebrand U, Shin D, Willenberg S, Behme S, Klawonn F, Koster M, Hauser H, Wirth D. Single-Cell Analysis Reveals Heterogeneity in Onset of Transgene Expression from Synthetic Tetracycline-Dependent Promoters. Biotechnol J. 2015;10(2):323-31. Epub 2015/01/15.

2014

Rand U, Hillebrand U, Sievers S, Willenberg S, Koster M, Hauser H, Wirth D. Uncoupling of the Dynamics of Host-Pathogen Interaction Uncovers New Mechanisms of Viral Interferon Antagonism at the Single-Cell Level. Nucleic Acids Res. 2014;42(13):e109.

Lipps C, May T, Wirth D. 2.1 Generation of Cell Lines and Biotechnological Applications. Animal Cell Biotechnology In Biologics Production2014.

Lieber D, Hochdorfer D, Stoehr D, Schubert A, Lotfi R, May T, Wirth D, Sinzger C. A Permanently Growing Human Endothelial Cell Line Supports Productive Infection with Human Cytomegalovirus under Conditional Cell Growth Arrest. Biotechniques. 2014;59(3):127-36. Epub 2014/01/01.

Kruse N, Spencer S, Wirth D. 3.4 Rational Approaches for Transgene Expression: Targeted Integration and Episomal Maintenance. Animal Cell Biotechnology . In Biologics Production2014.

Dag F, Dolken L, Holzki J, Drabig A, Weingartner A, Schwerk J, Lienenklaus S, Conte I, Geffers R, Davenport C, Rand U, Koster M, Weiss S, Adler B, Wirth D, Messerle M, Hauser H, Cicin-Sain L. Reversible Silencing of Cytomegalovirus Genomes by Type I Interferon Governs Virus Latency. PLoS Pathog. 2014;10(2):e1003962.

2013

Lipps C, May T, Hauser H, Wirth D. Eternity and Functionality - Rational Access to Physiologically Relevant Cell Lines. Biol Chem. 2013;394(12):1637-48.

Haenebalcke L, Goossens S, Naessens M, Kruse N, Farhang Ghahremani M, Bartunkova S, Haigh K, Pieters T, Dierickx P, Drogat B, Nyabi O, Wirth D, Haigh JJ. Efficient Rosa26-Based Conditional and/or Inducible Transgenesis Using Rmce-Compatible F1 Hybrid Mouse Embryonic Stem Cells. Stem Cell Rev. 2013;9(6):774-85.

Haenebalcke L, Goossens S, Dierickx P, Bartunkova S, D'Hont J, Haigh K, Hochepied T, Wirth D, Nagy A, Haigh JJ. The Rosa26-Ipsc Mouse: A Conditional, Inducible, and Exchangeable Resource for Studying Cellular (De)Differentiation. Cell Rep. 2013;3(2):335-41.

Dag F, Weingartner A, Butueva M, Conte I, Holzki J, May T, Adler B, Wirth D, Cicin-Sain L. A New Reporter Mouse Cytomegalovirus Reveals Maintained Immediate-Early Gene Expression but Poor Virus Replication in Cycling Liver Sinusoidal Endothelial Cells. Virol J. 2013;10:197.

Cebula M, Ochel A, Hillebrand U, Pils MC, Schirmbeck R, Hauser H, Wirth D. An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by Cd8+ T Cells. PLoS One. 2013;8(7):e68720.

2006 - 2012

2012

Botezatu L, Sievers S, Gama-Norton L, Schucht R, Hauser H, Wirth D. Genetic Aspects of Cell Line Development from a Synthetic Biology Perspective. Adv Biochem Eng Biotechnol. 2012;127:251-84.

Cruz PE., Cruz HJS, Barcia RN, Santos M, Pohl S, Gilljam M, Dittmar K, Lindenmaier W, Alici E. Ex-vivo expansion of human mesenchymal stem cells. In: The CliniBook: Clinical gene transfer, 2012, O.Cohen-Haguenauer, ed. (Paris) pp. 111-117, ISBN: 2842541715

Lindenmaier W, Macke L, Meyring W, Garritsen HSP, Dittmar KEJ, Lachmann K, Thomas M. Closed bag cultivation systems for the production of gene modified dendritic cells and MSC for clinical use. In: The CliniBook: Clinical gene transfer, 2012, O.Cohen-Haguenauer, ed. (Paris) pp. 121-127, ISBN: 2842541715.

2011

Wilke S, Groebe L, Maffenbeier V, Jager V, Gossen M, Josewski J, Duda A, Polle L, Owens RJ, Wirth D, Heinz DW, van den Heuvel J, Bussow K. Streamlining Homogeneous Glycoprotein Production for Biophysical and Structural Applications by Targeted Cell Line Development. PLoS One. 2011;6(12):e27829.

Schucht R, Lydford S, Andzinski L, Zauers J, Cooper J, Hauser H, Wirth D, May T. Rapid Establishment of G-Protein-Coupled Receptor-Expressing Cell Lines by Site-Specific Integration. J Biomol Screen. 2011;16(3):323-31.

Sandhu U, Cebula M, Behme S, Riemer P, Wodarczyk C, Metzger D, Reimann J, Schirmbeck R, Hauser H, Wirth D. Strict Control of Transgene Expression in a Mouse Model for Sensitive Biological Applications Based on Rmce Compatible Es Cells. Nucleic Acids Res. 2011;39(1):e1.

Lyszkiewicz M, Zietara N, Rohde M, Gekara NO, Jablonska J, Dittmar KE, Weiss S. Sign-R1+Mhc Ii+ Cells of the Splenic Marginal Zone--a Novel Type of Resident Dendritic Cells. J Leukoc Biol. 2011;89(4):607-15. Epub 2011/01/07.

Lohmeyer JA, Liu F, Kruger S, Lindenmaier W, Siemers F, Machens HG. Use of Gene-Modified Keratinocytes and Fibroblasts to Enhance Regeneration in a Full Skin Defect. Langenbecks Arch Surg. 2011;396(4):543-50. Epub 2011/03/04.

Lindenmaier W, Lachmann K, Meyring W, Garritsen H, Thomas M, Dittmar K. Innenbeschichtung Von Beuteln Für Die Kultur Adhärenter Humaner Zellen. BIOspektrum. 2011;17(1):32-4.

Lachmann K, Dohse A, Thomas M, Pohl S, Meyring W, Dittmar KEJ, Lindenmeier W, Klages CP. Surface Modification of Closed Plastic Bags for Adherent Cell Cultivation. European Physical Journal-Applied Physics. 2011;55(1).

Gama-Norton L, Botezatu L, Herrmann S, Schweizer M, Alves PM, Hauser H, Wirth D. Lentivirus Production Is Influenced by Sv40 Large T-Antigen and Chromosomal Integration of the Vector in Hek293 Cells. Hum Gene Ther. 2011;22(10):1269-79.

Carrondo M, Panet A, Wirth D, Coroadinha AS, Cruz P, Falk H, Schucht R, Dupont F, Geny-Fiamma C, Merten OW, Hauser H. Integrated Strategy for the Production of Therapeutic Retroviral Vectors. Hum Gene Ther. 2011;22(3):370-9.

Alkharsah KR, Singh VV, Bosco R, Santag S, Grundhoff A, Konrad A, Sturzl M, Wirth D, Dittrich-Breiholz O, Kracht M, Schulz TF. Deletion of Kaposi's Sarcoma-Associated Herpesvirus Flice Inhibitory Protein, Vflip, from the Viral Genome Compromises the Activation of Stat1-Responsive Cellular Genes and Spindle Cell Formation in Endothelial Cells. J Virol. 2011;85(19):10375-88.

2010

Surdziel E, Eder M, Scherr M. Lentivirus-Mediated Antagomir Expression. Immunotherapy of Cancer: Methods and Protocols. 2010;667:237-48. Epub 2010/09/10.

Shahab-Osterloh S, Witte F, Hoffmann A, Winkel A, Laggies S, Neumann B, Seiffart V, Lindenmaier W, Gruber AD, Ringe J, Haupl T, Thorey F, Willbold E, Corbeau P, Gross G. Mesenchymal Stem Cell-Dependent Formation of Heterotopic Tendon-Bone Insertions (Osteotendinous Junctions). Stem Cells. 2010;28(9):1590-601.

Nehlsen K, Herrmann S, Zauers J, Hauser H, Wirth D. Toxin-Antitoxin Based Transgene Expression in Mammalian Cells. Nucleic Acids Res. 2010;38(5):e32.

May T, Butueva M, Bantner S, Markusic D, Seppen J, MacLeod RA, Weich H, Hauser H, Wirth D. Synthetic Gene Regulation Circuits for Control of Cell Expansion. Tissue Eng Part A. 2010;16(2):441-52.

Macke L, Garritsen HS, Meyring W, Hannig H, Pagelow U, Wormann B, Piechaczek C, Geffers R, Rohde M, Lindenmaier W, Dittmar KE. Evaluating Maturation and Genetic Modification of Human Dendritic Cells in a New Polyolefin Cell Culture Bag System. Transfusion. 2010;50(4):843-55.

Loew R, Meyer Y, Kuehlcke K, Gama-Norton L, Wirth D, Hauser H, Stein S, Grez M, Thornhill S, Thrasher A, Baum C, Schambach A. A New Pg13-Based Packaging Cell Line for Stable Production of Clinical-Grade Self-Inactivating Gamma-Retroviral Vectors Using Targeted Integration. Gene Ther. 2010;17(2):272-80.

Garritsen HS, Macke L, Meyring W, Hannig H, Pagelow U, Wormann B, Geffers R, Dittmar KE, Lindenmaier W. Efficient Generation of Clinical-Grade Genetically Modified Dendritic Cells for Presentation of Multiple Tumor-Associated Proteins. Transfusion. 2010;50(4):831-42.

Gama-Norton L, Herrmann S, Schucht R, Coroadinha AS, Low R, Alves PM, Bartholomae CC, Schmidt M, Baum C, Schambach A, Hauser H, Wirth D. Retroviral Vector Performance in Defined Chromosomal Loci of Modular Packaging Cell Lines. Hum Gene Ther. 2010;21(8):979-91.

2009

Dogan Y, Ganser A, Scherr M, Eder M. Quantification of Transforming Capacity and Cooperation of Defined Genetic Alterations in Myeloid Malignancies. Exp Hematol. 2010;38(1):11-9. Epub 2009/10/20.

Dittmar KE, Simann M, Zghoul N, Schon O, Meyring W, Hannig H, Macke L, Dirks WG, Miller K, Garritsen HS, Lindenmaier W. Quality of Cell Products: Authenticity, Identity, Genomic Stability and Status of Differentiation. Transfus Med Hemother. 2010;37(2):57-64. Epub 2010/08/26.

Spanholtz T, Maichle A, Niedworok C, Stoeckelhuber BM, Kruger S, Wedel T, Aach T, Middeler G, Hellwig-Burgel T, Bader A, Krengel S, Muller OJ, Franz WM, Lindenmaier W, Machens HG. Timing and Targeting of Cell-Based Vegf165 Gene Expression in Ischemic Tissue. J Surg Res. 2009;151(1):153-62.

Scherr M, Venturini L, Eder M. Knock-Down of Gene Expression in Hematopoietic Cells. Methods Mol Biol. 2009;506:207-19.

Nehlsen K, Schucht R, da Gama-Norton L, Kromer W, Baer A, Cayli A, Hauser H, Wirth D. Recombinant Protein Expression by Targeting Pre-Selected Chromosomal Loci. BMC Biotechnol. 2009;9:100.

2008

May T, Eccleston L, Herrmann S, Hauser H, Goncalves J, Wirth D. Bimodal and Hysteretic Expression in Mammalian Cells from a Synthetic Gene Circuit. PLoS One. 2008;3(6):e2372.

Ma B, Wang L, von Wasielewski R, Lindenmaier W, Dittmar KE. Serial Sectioning and Three-Dimensional Reconstruction of Mouse Peyer's Patch. Micron. 2008;39(7):967-75.

Ma B, Lin Z, Winkelbach S, Lindenmaier W, Dittmar KE. Automatic Registration of Serial Sections of Mouse Lymph Node by Using Image-Reg. Micron. 2008;39(4):387-96.

Klopper J, Lindenmaier W, Fiedler U, Mehlhorn A, Stark GB, Finkenzeller G. High Efficient Adenoviral-Mediated Vegf and Ang-1 Gene Delivery into Osteogenically Differentiated Human Mesenchymal Stem Cells. Microvasc Res. 2008;75(1):83-90.

2007

Wirth D, Gama-Norton L, Riemer P, Sandhu U, Schucht R, Hauser H. Road to Precision: Recombinase-Based Targeting Technologies for Genome Engineering. Curr Opin Biotechnol. 2007;18(5):411-9.

Scherr M, Venturini L, Battmer K, Schaller-Schoenitz M, Schaefer D, Dallmann I, Ganser A, Eder M. Lentivirus-Mediated Antagomir Expression for Specific Inhibition of Mirna Function. Nucleic Acids Res. 2007;35(22):e149.

May T, Hauser H, Wirth D. In Vitro Expansion of Tissue Cells by Conditional Proliferation. Methods Mol Med. 2007;140:1-15.

Ma B, Zimmermann T, Rohde M, Winkelbach S, He F, Lindenmaier W, Dittmar KE. Use of Autostitch for Automatic Stitching of Microscope Images. Micron. 2007;38(5):492-9.

Ma B, von Wasielewski R, Lindenmaier W, Dittmar KE. Immmunohistochemical Study of the Blood and Lymphatic Vasculature and the Innervation of Mouse Gut and Gut-Associated Lymphoid Tissue. Anat Histol Embryol. 2007;36(1):62-74.

Ma B, Jablonska J, Lindenmaier W, Dittmar KE. Immunohistochemical Study of the Reticular and Vascular Network of Mouse Lymph Node Using Vibratome Sections. Acta Histochem. 2007;109(1):15-28.

Ma B, He F, Jablonska J, Winkelbach S, Lindenmaier W, Zeng AP, Dittmar KE. Six-Color Segmentation of Multicolor Images in the Infection Studies of Listeria Monocytogenes. Microsc Res Tech. 2007;70(2):171-8.

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