Milena Bellin

• 

  What are the pro-arrhythmic mechanisms underlying inherited cardiac diseases leading to sudden cardiac death?
  Can we use human pluripotent stem cells to model complex cardiac diseases and detect in vitro the phenotypic variability seen in patients?

  Our laboratory focuses on the use of human pluripotent stem cells to create in vitro models of human inherited cardiac diseases, to develop drug screening platforms and to build multicellular cardiac microtissues

  Background

  Research

  Group Members

  Key Publications

  The human heart is a complex organ, where distinct and specialised cells are anatomically and functionally organised during the first stages of embryonic development. Beside cardiomyocytes, the non-cardiomyocyte population represents a large proportion of the cells. This includes the epicardium, the endocardium, cardiac fibroblasts, (para)sympathetic nerve cells, smooth muscle and endothelial cells, and immune cells. All of these cell types play critical roles contributing to both normal and pathological heart physiology.

  Human induced pluripotent stem cells (hiPSCs) are remarkable in their capacity to differentiate into any cell type of the body. hiPSCs derived from patients with genetic cardiovascular disorders can be differentiated into cells of the heart and provide human models that can be used to understand pathophysiology of the disease, find new therapeutics and strategies for disease prevention.

  Our lab has successfully applied hiPSC-derived cardiomyocytes to study cardiac arrhythmia syndromes and used gene editing technology to reveal the causative effect of gene mutations. Our commitment is now to create advanced hiPSC-models for precision medicine in the context of lethal human heart disease. By combining exceptional expertise in stem cell, cardiac arrhythmia, drug development and tissue engineering we work towards building advanced hiPSC models to decipher cardiac disease with cellular and personalised accuracy.

  Cardiac ion channel diseases

  Channelopathies are cardiac arrhythmias caused by mutations in ion channel genes. We use cardiomyocytes from hiPSCs to study the molecular and electrical mechanisms underlying arrhythmia and to build platforms that could assist in the identification of anti-arrhythmic drugs.

  

  Fig. 1. hiPSC-derived cardiomyocytes.

  Complex cardiovascular diseases

  Complex cardiovascular diseases involve the contribution of multiple cell types in disease onset and progression. We differentiate hiPSCs into cardiomyocytes, cardiac endothelial cells, and cardiac fibroblasts and combine them in a three-dimensional structure that we call “cardiac microtissue” or “mini-heart”.  We then use cutting-edge technology to assess the functional, electrical, metabolic, and molecular behaviour of the tissue, under normal or disease conditions.

  

  Fig. 2. Cardiac microtissue or “mini-heart” from hiPSCs.

  Daniele Ottaviani - postdoc

  Key Publications

   

  1. Giacomelli E, Meraviglia V, Campostrini G, Cochrane A, Cao X, van Helden RWJ, Krotenberg Garcia A, Mircea M, Kostidis S, Davis RP, van Meer BJ, Jost CR, Koster AJ, Mei H, Míguez DG, Mulder AA, Ledesma-Terrón M, Pompilio G, Sala L, Salvatori DCF, Slieker RC, Sommariva E, de Vries AAF, Giera M, Semrau S, Tertoolen LGJ, Orlova VV, Bellin M, Mummery CL. Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease. Cell Stem Cell. 2020
  2. Chen X, Tasca F, Wang Q, Liu J, Janssen JM, Brescia MD, Bellin M, Szuhai K, Kenrick J, Frock RL, Gonçalves MAFV. Expanding the editable genome and CRISPR-Cas9 versatility using DNA cutting-free gene targeting based on in trans paired nicking. Nucleic Acids Res. 2020
  3. Sala L, Ward-van Oostwaard D, Tertoolen LGJ, Mummery CL, Bellin M. Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs). J Vis Exp. 2017
  4. Giacomelli E, Bellin M, Sala L, van Meer BJ, Tertoolen LG, Orlova VV, Mummery Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells. Development. 2017
  5. Sala L, Yu Z, Ward-van Oostwaard D, van Veldhoven JP, Moretti A, Laugwitz KL, Mummery CL, IJzerman AP, Bellin M. A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med. 2016
  6. Birket MJ, Ribeiro MC, Verkerk AO, Ward D, Leitoguinho AR, den Hartogh SC, Orlova VV, Devalla HD, Schwach V, Bellin M, Passier R, Mummery CL. Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells. Nat Biotechnol. 2015
  7. Zhang M, D'Aniello C, Verkerk AO, Wrobel E, Frank S, Ward-van Oostwaard D, Piccini I, Freund C, Rao J, Seebohm G, Atsma DE, Schulze-Bahr E, Mummery CL, Greber B, Bellin M. Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci U S A. 2014
  8. Bellin M, Casini S, Davis RP, D'Aniello C, Haas J, Ward-van Oostwaard D, Tertoolen LG, Jung CB, Elliott DA, Welling A, Laugwitz KL, Moretti A, Mummery CL. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J. 2013
  9. Moretti A*, Bellin M*, Welling A*, Jung CB, Lam JT, Bott-Flügel L, Dorn T, Goedel A, Höhnke C, Hofmann F, Seyfarth M, Sinnecker D, Schömig A, Laugwitz KL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. NEngl J Med. 2010
  10. Moretti A*, Bellin M*, Jung CB*, Thies TM, Takashima Y, Bernshausen A, Schiemann M, Fischer S, Moosmang S, Smith AG, Lam JT, Laugwitz KL. Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J. 2010

   

  Full publication list:

  https://pubmed.ncbi.nlm.nih.gov/?term=milena%20bellin&sort=date

  Milena Bellin

  

  MILENA BELLIN

   

  • PhD: CRIBI Biotechnology Center, University of Padova, Italy (2003-2006)
  • Postdoc: CRIBI Biotechnology Center, University of Padova, Italy (2006-2008)
  • Postdoc: Cardiology Division, Klinikum Rechts der Isar, Technical University of Munich, Germany (2008-2010)
  • Senior research fellow and Marie Curie fellow: Dept. of Anatomy and Embryology, Leiden University Medical Center, The Netherlands (2010-2016)
  • Assistant Professor and Group Leader: Dept. of Anatomy and Embryology, Leiden University Medical Center, The Netherlands (since 2016)
  • Assistant Professor: Dept. of Biology, University of Padova, Italy (since 2019)
  • Principal Investigator: Veneto Institute of Molecular Medicine, Padova, Italy (since 2019)

   

   

  SELECTED AWARDS

   

  • 2005 & 2006 – EMBO fellowships for EMBO Practical Courses
  • 2010 – Young Investigator Award Competition, 8th Dutch-German Joint Meeting of the Molecular Cardiology Working Groups, The Netherlands
  • 2012 – EU FP7 Marie Curie Intra-European Fellowship for Career Development
  • 2016 – FEBS Anniversary Prize for outstanding achievements in Biochemistry & Molecular Biology

  CURRENT FUNDINGS

  • ERC Consolidator Grant
  • Friedreich’s Ataxia Research Alliance Research Grant