Department of Pathology and Laboratory Medicine Spring 2015 Seminar Series: Friday, February 6,
Wellington V. Cardoso, M.D., Ph.D.
Professor of Medicine and Pathology & Laboratory Medicine
Director, Lung Development Program,
Associate Director, Pulmonary Center,
Boston University School of Medicine,
715 Albany Street R-304,
Boston, MA 02118
Phone: (617) 638-6198
FAX : (617) 536-8093
University of Brasilia (Brazil) M.D. Medicine
University of Brasilia (Brazil) Residency Pathology
University of Sao Paulo (Brazil) Ph.D. Pathology
University of British Columbia (Vancouver/Canada) Postdoc Pathology
Boston University, Pulmonary Center (Boston, MA) Postdoc Pulmonary Biology
• Lung development, stem cell, organogenesis, growth factor signaling, gene regulation
Our research is focused on the mechanisms that regulate the development of the respiratory system in the mammalian embryo. This process initiates early in organogenesis with the establishment of respiratory cell fate in the foregut endoderm and formation of the lung and tracheal primordia. The lung then develops into a tree-like system of epithelial tubules intertwined with vascular structures, which ultimately gives rise to the airways and alveoli.
We are investigating how respiratory progenitor cells are initially specified in the foregut and how they generate a wide diversity of cell types characteristic of the mature lung. We use functional mouse genetic approaches, organ and cell culture, genome wide screen, in situ hybridization and other strategies to study the role of specific pathways in the developmental programs of the lung. This research provides insights into basic mechanisms of lung development and stem cell/progenitor cell biology. It also has an impact on our understanding of the pathogenesis of conditions such as lung immaturity and pulmonary hypoplasia, and mechanisms of repair in the adult lung.
Retinoic acid signaling in lung development:
Disruption of retinoic acid (RA) signaling in Vitamin A deficient embryos results in major developmental abnormalities including tracheoesophageal fistula, lobation defects, lung hypoplasia and, in its severest form, failure to form lungs. Our studies reveal that RA signaling is highly active at the onset of lung development. We are using genetic and pharmacological (RA antagonist BMS) models of RA deficiency to investigate how RA influences lung progenitor cell behavior and induction of the lung primordium.
Fgf10 regulation of lung progenitor cell expansion and bud formation:
Local expression of Fgf10 in the foregut mesoderm is required to activate Fgfr2b signaling in lung epithelial progenitors and form the lung primordium. Fgf10 null mice form trachea but not the lung. We have been studying mechanisms that regulate Fgf10 expression in the lung mesodem and the events that result from Fgf activation in lung epithelial buds. We have identified by genome-wide screen and are currently characterizing a number of Fgf10-Fgfr2b targets, including genes involved in cell rearrangement, cell migration and tumorigenesis.
FGF-heparan sulfate interactions in lung epithelial morphogenesis:
Heparan sulfate (HS) proteoglycans modulate the biological activity of a number of growth factors Fgf, Wnt, and Tgf beta in development, homeostasis and cancer. We have been studying the role of HS sulfation mediated by HS 6-O sulfotransferases in pre- and postnatal lung development.
Notch signaling in lung cell fate:
Studies in a number of biological systems show that Notch signaling controls cell fate decisions, establishment of asymmetries, and timing of differentiation. We are exploring the role of Notch in balancing proximal-distal cell fates in the respiratory epithelium at early and late developmental stages.
RECENT PUBLICATIONS (2004-2008)
- Desai T, Malpel S, Flentke GR, Smith SM, and Cardoso WV. Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut. Dev. Biol 273:418-435, 2004.
- Jones JE, Walker JL, Song Y, Weiss N, Cardoso WV, Tuder RM, Loscalzo J, and Zhang Y. Effect of 5-Lipoxygenase on the Development of Pulmonary Hypertension in Rats Am.J. Physiol. 286:H1775-84, 2004.
- Lü J, Qian J, Izvolsky KI, Cardoso WV. Global analysis of genes differentially expressed in branching and non-branching regions of the mouse embryonic lung. Dev. Biol 273:402-415, 2004.
- Sedita J, Izvolsky K, and Cardoso WV. Differential expression of heparan sulfate 6-O-sulfotransferase isoforms in the mouse embryo suggests distinctive roles during organogenesis Dev. Dyn. 231:782-794, 2004.
- Lu J, Izvolsky KI, Qian J, and Cardoso WV. Identification of FGF10 targets in the embryonic lung epithelium during bud morphogenesis. J. Biol Chem 280:4934-4841, 2005.
- Lü J, Qian J, Tang X, Li C, Chen F, Cardoso, WV. Differential expression of components of the microRNA machinery during mouse organogenesis. Biochem. Biophys. Research Com. 334:319-323, 2005.
- Desai T, Chen F., Lu J, Qian J, Niederreither K., Dollé, P., Chambon, P., and Cardoso WV. Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis. Dev. Biol., 291:12-24, 2006.
- Cardoso, WV and Lu, J. Regulation of early lung development: questions, facts and controversies. Development 133: 1161-1624, 2006.
- Wang Z, Dollé,P, Cardoso, WV, Niederreither K. Retinoic Acid Regulates Morphogenesis and Patterning of Posterior Foregut Derivatives. Dev. Biol. 297:433–445, 2006.
- Lü J, Qian J, Keppler D, Cardoso WV. Cathespin H is an FGF10 Target Involved in BMP4 Degradation during Mouse Lung Branching Morphogenesis J. Biol Chem 282:22176–22184, 2007.
- Chen F., Desai T., Qian J., Niederreither K., Lu J, and Cardoso WV. Inhibition of Tgf beta signalling by endogenous retinoic acid is essential for primary lung bud induction Development 134: 2969-2979, 2007.
- Izvolsky KI, Lu J, Martin G, Albrecht K, and Cardoso WV. Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis. Genesis 46:8-18, 2008.
- Lu P, Lu J, Cardoso WV, and Vaziri C. The Matricellular Factor The SPARC-Related Factor SMOC-2 Promotes Growth Factor-Induced Cyclin D1 Expression and DNA Synthesis via Integrin-Linked Kinase (ILK). Mol. Biol. Cell. 19:248-261, 2008.
- Jean JC, Lü J, Joyce-Brady M, Cardoso WV. Regulation of Fgf10 Gene Expression in Mesenchymal Cells from Mouse Lung. J. Cell Biochem., 103:1886-1894, 2008.
- Franks T, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Engelhardt J, Frid M, Erica H, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, Serge J, Sunday ME, Voynow JA, Weinstein BM,Whitsett J A, Williams MC. NHLBI WORKSHOP – Resident Cellular Components of the Human Lung: Current Knowledge and Goals for Research on Cell Phenotyping and Function. Proc. Am. Thor. Soc. 2008 (in press)
- Cardoso WV, Whitsett JA. Resident Cellular Components of the Lung: Developmental Aspects. Proc. Am. Thor. Soc. 2008 (in press)