Michelina Iacovino, PhD
Assistant Professor of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine at UCLA
Development of vascular endothelium and stem cell therapies
Research DescriptionThe cardiovascular and blood system are the first organs to develop in the embryos, due their vital function to bring oxygen and nutrients to the fast growing embryo. Defects in these system cause death of the developing embryos. Both of them originate from the same embryonic tissue, the mesoderm very early in development. Differentiation of ES cells mimic quite faithfully the early patterning of mesoderm, with the advantage of having plenty of material for molecular analysis. We are interested in understanding the role of Hox Genes, essential transcription factors for organogenesis, in the developing heart and blood system.
One project founded in the lab aims at understanding the role of HoxA3 during Cardiac Development (SDG9260007) HoxA3 knockout is one of the animal model for the Di George syndrome which affect mainly the outflow tract of the heart and the pharyngeal arches development. HoxA3 upregulation causes repression of cardiac differentiation in vitro most likely due to the regulation of the notch pathway.
HEMATOPOIETIC STEM CELL (HSC) GENERATION:
The other project in the lab regards the generation of HSC during development. Hematopoietic HSC transplantation has saved million of life, but difficulties in finding matching donors and graft versus host disease are serious limitation to completely cure blood malignancy. A source of cells for autologous transplantation will be a solution for both problems. Pluripotent Stem cell therapy is a future solution, but is still unclear the mechanism governing HSC generation from embryonic tissue.
HoxA3 is a regulator of HSC, represses the expression of Runx1 in vitro and in vivo, thus controls the release of HSC from hemogenic endothelium. Why HoxA3 controls HSC generation is still unclear. We are testing the hypothesis that HoxA3 plays a role in the commitment of endothelial cells toward hemogenic endothelium, thus preventing early expression of Runx1. We will be using for this project gain and loss of function approaches, both in the embryo as well as ES cell differentiation. Understanding the molecular mechanism of HSC generation will contribute to scientific effort to use stem cells therapy for malignant disease.
- PhD, 2004, University of Molise, Campobasso, Italy
Recent and/or Significant Publications
- Borges L, Iacovino M, Mayerhofer T, Koyano-Nakagawa N, Baik J, Garry DJ, Kyba M, Letarte M, Perlingeiro RC. A critical role for endoglin in the emergence of blood during embryonic development. Blood. 2012 Jun 7;119(23):5417-28. Epub 2012 Apr 24.
- Iacovino M, Bosnakovski D, Fey H, Rux D, Bajwa G, Mahen E, Mitanoska A, Xu Z, Kyba M. Inducible cassette exchange: a rapid and efficient system enabling conditional gene expression in embryonic stem and primary cells. Stem Cells. 2011 Oct;29(10):1580-8.
- Iacovino M, Chong D, Szatmari I, Hartweck L, Rux D, Caprioli A, Cleaver O, Kyba M. HoxA3 is an apical regulator of haemogenic endothelium. Nat Cell Biol. 2011 Jan;13(1):72-8. Epub 2010 Dec 19.