This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 99/8/861    most recent 01.RES.0000245188.41002.2cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paruchuri, S. Articles by Bischoff, J. Search for Related Content PubMed PubMed Citation Articles by Paruchuri, S. Articles by Bischoff, J. Related Collections Angiogenesis Cardiac development Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation Research. 2006;99:861.)
© 2006 American Heart Association, Inc.

Cellular Biology

Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-ß₂

Sailaja Paruchuri, Jeong-Hee Yang, Elena Aikawa, Juan M. Melero-Martin, Zia A. Khan, Stavros Loukogeorgakis, Frederick J. Schoen, Joyce Bischoff

From the Department of Surgery (S.P., J.-H.Y., J.M.M.-M., Z.A.K., S.L., J.B.), Vascular Biology Program, Children’s Hospital Boston and Harvard Medical School; and Department of Pathology (E.A., F.J.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass. Current address for S.P.: Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, Mass. Current address for E.A.: Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown. Current address for S.L.: Institute for Child Health and Great Ormond Street Hospital for Children, University College London, UK.

Correspondence to Joyce Bischoff, PhD, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail joyce.bischoff{at}childrens.harvard.edu

In situ analysis of fetal semilunar valve leaflets has revealed cells coexpressing endothelial and mesenchymal markers along the endothelium, with diminished frequency seen in adult valves. To determine whether such cells are progenitor cells, we isolated clonal populations from human pulmonary valves. The clones expressed endothelial markers but showed potential to further differentiate into endothelium in response to vascular endothelial growth factor (VEGF)-A. When exposed to transforming growth factor (TGF)-ß₂, individual clones adopted a mesenchymal phenotype to varying degrees and expressed markers of endothelial to mesenchymal transformation (EMT). Both VEGF- and TGFß₂–induced phenotypic changes were partially reversible, indicating the plasticity of these cells. When challenged with VEGF or TGFß₂, a hierarchy of endothelial/mesenchymal potential could be seen among the clonal populations: cells initially closer to an endothelial phenotype showed a strong response to TGFß₂ that could be inhibited by VEGF, whereas cells closer to a mesenchymal phenotype responded to TGFß₂ but were resistant to endothelial-inducing effects of VEGF. These findings suggest the presence of bipotential valve progenitor cells with ability to differentiate into either endothelial or interstitial cells of the valve leaflet. Understanding the differentiation potential and function of these cells may be important for understanding heart valve disease and may also be applied to current paradigms for creating tissue-engineered heart valves.

Key Words: cell culture • endothelial cell differentiation • endothelial cells • heart valves • progenitor cells • transdifferentiation • vascular endothelial growth factor • vascular endothelium

This article has been cited by other articles:

				M. D. Combs and K. E. Yutzey Heart Valve Development: Regulatory Networks in Development and Disease Circ. Res., August 28, 2009; 105(5): 408 - 421. [Abstract] [Full Text] [PDF]

				J. P. Dal-Bianco, E. Aikawa, J. Bischoff, J. L. Guerrero, M. D. Handschumacher, S. Sullivan, B. Johnson, J. S. Titus, Y. Iwamoto, J. Wylie-Sears, et al. Active Adaptation of the Tethered Mitral Valve: Insights Into a Compensatory Mechanism for Functional Mitral Regurgitation Circulation, July 28, 2009; 120(4): 334 - 342. [Abstract] [Full Text] [PDF]

				M. Chaput, M. D. Handschumacher, F. Tournoux, L. Hua, J. L. Guerrero, G. J. Vlahakes, and R. A. Levine Mitral Leaflet Adaptation to Ventricular Remodeling: Occurrence and Adequacy in Patients With Functional Mitral Regurgitation Circulation, August 19, 2008; 118(8): 845 - 852. [Abstract] [Full Text] [PDF]

				A. C. Liu, V. R. Joag, and A. I. Gotlieb The Emerging Role of Valve Interstitial Cell Phenotypes in Regulating Heart Valve Pathobiology Am. J. Pathol., November 1, 2007; 171(5): 1407 - 1418. [Abstract] [Full Text] [PDF]

				V. L. Sales, G. C. Engelmayr Jr, J. A. Johnson Jr, J. Gao, Y. Wang, M. S. Sacks, and J. E. Mayer Jr Protein Precoating of Elastomeric Tissue-Engineering Scaffolds Increased Cellularity, Enhanced Extracellular Matrix Protein Production, and Differentially Regulated the Phenotypes of Circulating Endothelial Progenitor Cells Circulation, September 11, 2007; 116(11_suppl): I-55 - I-63. [Abstract] [Full Text] [PDF]

				I. Yana, H. Sagara, S. Takaki, K. Takatsu, K. Nakamura, K. Nakao, M. Katsuki, S.-i. Taniguchi, T. Aoki, H. Sato, et al. Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells J. Cell Sci., May 1, 2007; 120(9): 1607 - 1614. [Abstract] [Full Text] [PDF]