ditadi.andrea@hsr.it

The focus of our lab is to understand and recapitulate normal and pathological human hematopoietic development, at the signaling and genetic level, with the goal of generating blood cell products, to be used in the regenerative medicine framework. Most of the studies harness the potential of human pluripotent stem cells (hPSC; comprising human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC)). The ability to generate functional blood cells from hPSCs in culture would represent an important step forward, as it would provide an unlimited source of these cells for therapeutic applications as well as a model for studying human hematopoietic development and disease in vitro.

Curriculum Vitae

  • RESEARCH POSITIONS

2010 – 2016   Group Leader at the SR-TIGET (San Raffaele – Telethon Institute for Gene Therapy)

2010 – 2016   Postdoctoral fellow in the laboratory of Dr. Gordon Keller at the McEwen Centre for Regenerative Medicine,  Toronto, Canada

2009      Postdoctoral fellow in Dr. André-Schmutz lab at the unity INSERM U768 of “Groupe Hospitalier Necker – Enfants Malades”, Paris, France.

2005 – 2008:   Graduate student at the unity INSERM U768 of “Groupe Hospitalier Necker – Enfants Malades” in Paris, under the supervision of Dr. Marina Cavazzana

2003 – 2004    Undergraduate student at the Department of Biology, University of Padua, at the Gene Transfer Lab, under the supervision of Dr. L. Vitiello.

  • DEGREES and Academic qualifications

2008   Ph.D. in Developmental Molecular and Cell Biology (PhD school of “Genetics, Immunology, Infectiology and Development”) at University Réné Déscartes Paris V, France. Supervisor: Dr. Marina Cavazzana

2004   B.Sc/M.Sc in Medical Biotechnologies, University of Padua, final evaluation: Summa cum Laude. Supervisor: Dr. Libero Vitiello

 

  • ORAL COMMUNICATIONS

Oral presentation at international meetings (Keystones Symposia Hematopoiesis 2015; ISSCR 2015; PCBC 2015; ISEH 2012; PCBC 2012; Keystone symposia Hematopoiesis 2011)

Invited speaker at Max Plank Institute for Immunobiology and Epigenetics, Freiburg, GER; SR-TIGET, Milan, ITA; Center for Regenerative Therapies, Dresden, GER; Cambridge Stem Cell Institute, Cambridge, UK; Berlin Institute of Health, Berlin, GER; St. Jude’s Research Hospital, Memphis, USA; MRC Center for Regenerative Medicine, Edinburgh, UK; Center for Cronic Immunodeficiencies, Freiburg, GER; Imagine Institute, Paris, FRA.

 

  • Scholarships and Awards

2015    Keystone Symposia Scholarship

2010 – 2014  Magna-Golftown Postdoctoral Fellowship from the McEwen Centre for Regenerative Medicine

2006    EGIDE Scholarship Award from The French Ministry for Foreign Affairs

2005    Vinci Scholarship Award from The Italian-French University Association

2005 – 2008  Scholarship from the Italian Ministry of Research

 

  • Additional Professional Activities AND MEMBERSHIPS

2016 – present   Co-chair of ISSCR Junior Investigator Committee

2011 – 2015       ISSCR Junior Investigator Committee Member

2016 – present    The International Society for Stem Cell Research (ISSCR)

2012 – present    The Society for Hematology and Stem Cells (ISEH)

2010 – present    Progenitor Cell Biology Consortium (PCBC)

2010 – present    Stem Cell Network, Canada (SCN)

Research Activity

The success in generating HSC from hPSC will depend on our ability to accurately recapitulate key aspects of embryonic HSC formation in vitro. While significant progress in reprogramming and hPSC differentiation has enabled the production of diverse cell types comprising the hematopoietic system (Slukvin, 2013), the generation of HSC in vitro has not been achieved to date, being hampered by our inability to accurately recapitulate embryonic development. In particular, the major issues are represented by 1) the inability to accurately discriminate between progenitors of the two different embryonic hematopoietic programs (primitive and definitive); and 2) the poor understanding of the development of the progenitor cell population that gives rise to HSC in mammals. We therefore have focused on solving these two issues. We have first defined the onset of human definitive hematopoiesis, the program that gives rise to HSC, using hPSC (Kennedy et al., 2012). This work brought a new perspective on human hematopoiesis, as it demonstrated that both embryonic hematopoietic programs (primitive and definitive) are specified simultaneously very early during hPSC differentiation. These findings set the ground for a subsequent study that described the identification of the earliest progenitors of both hematopoietic programs (Sturgeon et al., 2014).

We then studied the emergence and the regulation of the progenitor population that gives rise to HSC. Time-lapse and lineage tracing experiments have demonstrated that, in the vertebrate embryo, blood cells originate from a specialized subpopulation of endothelial cells known as hemogenic endothelial cells (HEC), through a process commonly referred to as the endothelial-to-hematopoietic transition (EHT) (Bertrand et al., 2010; Boisset et al., 2010; Kissa and Herbomel, 2010). These progenitors are found in both the primitive and the definitive hematopoiesis but differ in their developmental potential. HSC are generated only during the definitive hematopoiesis in a Notch-dependent manner (Bigas et al., 2010).

Using the mouse as a model we first have uncovered the role of retinoic acid (RA) signaling in HSC development, demonstrating that in the mid-gestation mouse embryo RA signaling regulates the generation of HSC from HEC (Chanda et al., 2013). We then focused my attention on the characterization of hPSC-derived definitive HEC. In the vertebrate embryo HEC are associated with major arteries, which has led to the hypothesis that HEC represent a subpopulation of arterial vascular endothelial cells (VEC). However, through the detailed analysis of the emergence of the definitive hematopoietic program, we clearly demonstrated that hPSC-derived HEC can be clearly distinguished from VEC based on the expression of the surface markers CD34, CD73, CD184 and DLL4 (Ditadi et al., 2015). At a clonal level, hPSC-derived HEC are restricted to a CD34+CD73CD184DLL4 population that is capable of undergoing a NOTCH-dependent EHT to generate lymphoid, myeloid and erythroid progeny. These results demonstrated for the first time the isolation of a hPSC-derived true multilineage hematopoietic progenitor that gives rise to all the different blood lineages (Ditadi et al., 2015). These progenitors have been successfully used as a tool for investigating the emergence of inherited hematological conditions as well as acquired disorders like leukemias.

Collectively, these findings provide an ideal platform for understanding the regulation of hematopoietic development and the onset of hematological disorders. The long-term goal of our lab is to make a large contribution to the clinical application of hPSCs, generating both cell therapy products for regenerative medicine, and drug discovery screening tools for the treatment of hematopoietic disorders.

Publications

  • Ditadi A, Sturgeon CM. Directed differentiation of definitive hemogenic endothelium and hematopoietic progenitors from human pluripotent stem cells. Methods 2015; S1046-2023(15)30119-5.
  • Ditadi A, Sturgeon CM, Tober J, Awong G, Kennedy M, Phillips A, Azzola L, Ng ES, Stanley E, French DL, Cheng X, Gadue P, Speck N, Elefanty AG, Keller G. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat Cell Biol 2015;17(5):580-91.
  • Sturgeon CM, Ditadi A, Awong G, Kennedy M, Keller G. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat Biotechnol 2014;32(6):554-61.
  • Chanda B, Ditadi A, Iscove NN, Keller G. Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell 2013;155(1):215-27.
  • Sturgeon CM, Ditadi A, Clarke R, Keller G. Defining the path to hematopoietic stem cells. Nat Biotechnol 2013; 31:416-18.
  • Kennedy M, Awong G, Sturgeon CM, Ditadi A, LaMotte-Mohs R, Zuniga-Pflucker JC, Keller G. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep 2012; 27;2(6):1722-35.
  • Sturgeon CM, Chicha L, Ditadi A, Zhou Q, McGrath KE, Palis J, Hammond SM, Wang S, Olson EN, Keller G. Primitive erythropoiesis is regulated by miR-126 via nonhematopoietic Vcam-1(+) Cells. Dev Cell 2012; 23(1):45-57.
  • Rossi CA, Pozzobon M, Ditadi A, Archacka K, Gastaldello A, Sanna M, Franzin C, Malerba A, Milan G, Cananzi M, Schiaffino S, Campanella M, Vettor R, De Coppi P. Clonal characterization of muscle satellite cells: proliferation, metabolism and differentiation define an intrinsic heterogeneity. PLoS One 2010; 1;5(1):e8523.
  •  Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, Demerens-de Chappedelaine C, Morillon E, Valensi F, Simon-Stoos KL, Mullikin JC,  Noroski LM, Besse C, Wulffraat NM, Ferster A, Abecasis MM, Calvo F, Petit C, Candotti F, Abel L, Fischer A, Cavazzana-Calvo M. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness.  Nat Genet 2010; 41(1):106-11.
  • Ditadi A, de Coppi P, Picone O, Gautreau L, Smati R, Six E, Bonhomme D, Ezine  S, Frydman R, Cavazzana-Calvo M, Andre-Schmutz I. Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity. Blood 2009; 113(17):3953-60.
  • Vitiello L, Bassi N, Campagnolo P, Zaccariotto E, Occhi G, Malerba A, Pigozzo S, Reggiani C, Ausoni S, Zaglia T, Gamba P, Baroni MD, Ditadi AP. In vivo delivery of naked antisense oligos in aged mdx mice: analysis of dystrophin restoration in skeletal and cardiac muscle.  Neuromuscul Disord 2008; 18(8):597-605.
  • Pozzobon M, Piccoli M, Ditadi A, Bollini S, Destro R, André-Schmutz I, Masiero L, Lenzini E, Zanesco L, Petrelli L, Cavazzana-Calvo M, Gazzola MV, De Coppi P. Mesenchymal Stromal Cells Can Be Derived from Bone Marrow CD133(+) Cells: Implications for Therapy.  Stem Cells Dev 2009; 18(3):497-510
  • Grisafi D, Piccoli M, Pozzobon M, Ditadi A, Zaramella P, Chiandetti L, Zanon GF, Atala A, Zacchello F, Scarpa M, De Coppi P, Tomanin R. High transduction efficiency of human amniotic fluid stem cells mediated by adenovirus vectors.  Stem Cells Dev 2008; 17(5):953-62.
  • Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, Carraro G, Thiene G, Towbin JA, Danieli GA, Rampazzo A. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 2005; 65(2):366-73.