Embryonic Stem Cell-Derived Endothelial Cells May Lack Complete Functional Maturation in vitro

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Abstract

Stem cell therapies will only become clinically relevant if the stem cells differentiated in vitro function as their in vivo counterparts. Here, we employed our previously developed techniques for deriving endothelial cells (>96% purity) from mouse embryonic stem cells (ESC) and compared these with mouse aortic endothelial cells (MAEC) obtained from thoracic aortas. Immunocytochemical analysis of ESC-derived endothelial cells (EC) demonstrates that both cell types are positive for the EC markers endothelial nitric oxide synthase (eNOS), Flk-1, Flt-1, vascular endothelial cadherin (VEcad), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and CD34. However, ESC-derived EC express slightly lower levels of PECAM-1 and VE-cadherin, and significantly lower levels of acetylated low-density lipoprotein (LDL) uptake and von Willebrand factor. Although ESC-derived EC do express VE-cadherin, the VE-cadherin in the ESC-derived EC did not localize as well at the cell-cell junctions as in the MAEC. Interestingly, ESC-derived EC express much greater levels of the endothelial and hematopoietic stem cell marker CD34 and vasculogenic and angiogenic sprouting than MAEC. These results indicate that ESC-derived EC share some key characteristics of ‘mature’ EC, while retaining markers of alternate phenotypes including immature endothelium.

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Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors.

J. Yamashita, H Itoh, M Hirashima … (2000)

Interaction between endothelial cells and mural cells (pericytes and vascular smooth muscle) is essential for vascular development and maintenance. Endothelial cells arise from Flk1-expressing (Flk1+) mesoderm cells, whereas mural cells are believed to derive from mesoderm, neural crest or epicardial cells and migrate to form the vessel wall. Difficulty in preparing pure populations of these lineages has hampered dissection of the mechanisms underlying vascular formation. Here we show that Flk1+ cells derived from embryonic stem cells can differentiate into both endothelial and mural cells and can reproduce the vascular organization process. Vascular endothelial growth factor promotes endothelial cell differentiation, whereas mural cells are induced by platelet-derived growth factor-BB. Vascular cells derived from Flk1+ cells can organize into vessel-like structures consisting of endothelial tubes supported by mural cells in three-dimensional culture. Injection of Flk1+ cells into chick embryos showed that they can incorporate as endothelial and mural cells and contribute to the developing vasculature in vivo. Our findings indicate that Flk1+ cells can act as 'vascular progenitor cells' to form mature vessels and thus offer potential for tissue engineering of the vascular system.

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Multilineage differentiation from human embryonic stem cell lines.

J Odorico, Jay S. Kaufman, Andrew J. Thomson (2000)

Stem cells are unique cell populations with the ability to undergo both self-renewal and differentiation. A wide variety of adult mammalian tissues harbors stem cells, yet "adult" stem cells may be capable of developing into only a limited number of cell types. In contrast, embryonic stem (ES) cells, derived from blastocyst-stage early mammalian embryos, have the ability to form any fully differentiated cell of the body. Human ES cells have a normal karyotype, maintain high telomerase activity, and exhibit remarkable long-term proliferative potential, providing the possibility for unlimited expansion in culture. Furthermore, they can differentiate into derivatives of all three embryonic germ layers when transferred to an in vivo environment. Data are now emerging that demonstrate human ES cells can initiate lineage-specific differentiation programs of many tissue and cell types in vitro. Based on this property, it is likely that human ES cells will provide a useful differentiation culture system to study the mechanisms underlying many facets of human development. Because they have the dual ability to proliferate indefinitely and differentiate into multiple tissue types, human ES cells could potentially provide an unlimited supply of tissue for human transplantation. Though human ES cell-based transplantation therapy holds great promise to successfully treat a variety of diseases (e.g., Parkinson's disease, diabetes, and heart failure) many barriers remain in the way of successful clinical trials.

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Endothelial cells derived from human embryonic stem cells.

J Golub, Michal Amit-Kohn, Robert D. Langer … (2002)

Human embryonic stem cells have the potential to differentiate into various cell types and, thus, may be useful as a source of cells for transplantation or tissue engineering. We describe here the differentiation steps of human embryonic stem cells into endothelial cells forming vascular-like structures. The human embryonic-derived endothelial cells were isolated by using platelet endothelial cell-adhesion molecule-1 (PECAM1) antibodies, their behavior was characterized in vitro and in vivo, and their potential in tissue engineering was examined. We show that the isolated embryonic PECAM1+ cells, grown in culture, display characteristics similar to vessel endothelium. The cells express endothelial cell markers in a pattern similar to human umbilical vein endothelial cells, their junctions are correctly organized, and they have high metabolism of acetylated low-density lipoprotein. In addition, the cells are able to differentiate and form tube-like structures when cultured on matrigel. In vivo, when transplanted into SCID mice, the cells appeared to form microvessels containing mouse blood cells. With further studies, these cells could provide a source of human endothelial cells that could be beneficial for potential applications such as engineering new blood vessels, endothelial cell transplantation into the heart for myocardial regeneration, and induction of angiogenesis for treatment of regional ischemia.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2006

Publication date (Print): September 2006

Publication date (Electronic): 20 September 2006

Volume: 43

Issue: 5

Pages: 411-421

Affiliations

^aThe Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Ga., ^bSchool of Engineering, University of California, Merced, Calif., ^cThe Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Ga., ^dDivision of Cardiology, Emory University, Atlanta, Ga., ^eThe Woodruff School of Mechanical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Ga., USA

Article

Publisher ID: 94791 Other ID: J Vasc Res 2006;43:411–421

DOI: 10.1159/000094791

PubMed ID: 16877873

SO-VID: cdbdf33f-503d-4521-8d40-70834f8c25bc

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 15 March 2006

Date accepted : 31 May 2006

Page count

Figures: 8, References: 35, Pages: 11

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Embryonic Stem Cell-Derived Endothelial Cells May Lack Complete Functional Maturation in vitro

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Abstract

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Karger: Cardiovascular System

Most cited references 18

Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors.

Multilineage differentiation from human embryonic stem cell lines.

Endothelial cells derived from human embryonic stem cells.

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Cited by 9

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