Table Of ContentNOVEL ANGIOGENIC
MECHANISMS
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LA1THA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
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NOVEL ANGIOGENIC MECHANISMS: Role of Circulating Progenitor Endothelial Cells
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NOVEL ANGIOGENIC
MECHANISMS
Role of Circulating Progenitor
Endothelial Cells
Edited by
Nicanor I. Moldovan, Ph.D.
The Ohio State University
Columbus, Ohio
Springer Science+ Business Media, LLC
Library of Congress Cataloging-in-Publication Data
International Workshop "Novel Angiogenic Mechanisms" (2002: Columbus, Ohio)
Novel angiogenic mechanisms: role of circulating progenitor endothelial cells/edited by
Nicanor L Moldovan.
p. cm. - (Advances in experimental medici ne and biology; v. 522)
Proceedings of an international workshop held on April 16-17,2002 in Columbus, Ohio.
Includes bibliographical references and index.
ISBN 978-1-4613-4951-8 ISBN 978-1-4615-0169-5 (eBook)
DOI 10.1007/978-1-4615-0169-5
l. Vascular endothelium-Congresses. 2. Neovascularization-Congresses. 3. Stern
cells-Congresses. L Moldovan, Nicanor 1. II. Title. III. Advances in experimenatl
medici ne and biology; v. 522.
[DNLM: l. Neovascularization, Phyiologic-Congresses. 2. Angiogeneis
Factor-Congresses. 3. Endothelial Growth Factors-Congresses. WG 500 1615n 2003]
QPllO.V34 156 2002
612.l'3-dc21
2002043276
Proceedings of the International Workshop "Novel Angiogenic Mechanisms," held at Davis Heart and Lung
Research Institute in Columbus, OH. USA, on April 16-17. 2002.
ISBN 978-1-4613-4951-8
©2003 Springer Science+Business Media New York
Originally published by Kluwer AcademiclPlenum Publishers, New York in 2003
Softcover reprint ofthe hardcover 1 st edition 2003
AII rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any
means, electronic, mechanical, photocopying, microfilming, recording, or otherwise. without written
permission from the Publisher, with the exception of any material supplied specifically for the purpose of
being entered and executed on a computer system, for exclusive use by the purchaser of the work.
FOREWORD
New experimental observations often require fresh concepts for their interpretation,
and at times even changes of paradigms. This is the situation with the recent realization
that circulating endothelial progenitor cells may have an important contribution to the
maintenance and formation of new endothelium in adult organisms, in a surprisingly
wide variety of situations. The classical paradigm of angiogenesis, centered on the notion
of "sprouting" can hardly accommodate them. It was previously realized that it needs to
be "stretched out" to include alternative mechanisms of microvascular development, such
as intussusception and capillary fusion. However, a major debate where to reconsider the
sprouting mechanism, and to promote alternative views, did not take place yet. The
number of publications in this field increased exponentially in the last years.
Nevertheless, the concepts and notions so much needed to describe and to explain the
new observations are still scarce, and heterogeneous.
Within the larger community dedicated to the study of angiogenesis, the researchers
involved in investigation of circulating precursor endothelial cells biology represent a
subgroup with specific preoccupations and opinions. Many of them did not meet each
other so far, and no major scientific events have been dedicated before exclusively to
their interests.
For the above reasons, the idea to organize a symposium addressing the new
developments in angiogenesis research was received with enthusiasm by all those
involved in its preparation. This meeting became the International Workshop "Novel
Angiogenic Mechanisms", and was held on April 16-17, 2002, in the newly-opened
"Dorothy M. Davis" Heart and Lung Research Institute (DHLRI) of the Ohio State
University Medical Center in Columbus, Ohio, USA. This institution incorporates a solid
interest in angiogenesis and is committed to the support of most advanced developments
in cardiovascular and pulmonary medicine, thus it provided an ideal forum for interaction
and discussions.
The International Scientific Organizing Committeeof the Workshop, which provided
constant advice and support, included Dr. Peter H. Burri (Institute of Anatomy, Berne,
Switzerland), Dr. Christian C. Hauderschild (Department of Experimental Pathology,
J.H. Holland Laboratory, American Red Cross, Rockville, MD, USA), Dr. Klaus
Havemann (Institute for Molecular Biology and Tumor Research, Philips-University,
Marburg, Germany), and Dr. Nicholas A. Flavahan (DHLRI, The Ohio State University,
Columbus, OH, USA).
v
vi FOREWORD
A special mentioning deserves Dr. Peter Burri, for his enthusiasm and commitment
to this meeting from its conception.
During the preparation of the meeting, I received a substantial support from the
leadership of DHLRI (Dr. Jay Zweier and Dr. Mark Wewers), Department of Internal
Medicine (Dr. Michael Grever), College of Medicine and Public Health (Dr. Fred
Sanfilippo), and from the Center for Continuous Medical Education (Mr. Jon Hollet), for
which I am very grateful.
The preparation of the workshop benefited from the assistance provided by Melissa
Poulos, and could have not be completed without the benevolent participation and total
dedication of Mr. Laura Sladoje (Department of Ophthalmology).
Besides DHLRI, the following organizations and companies contributed with funds
to the covering of expenses incurred by the meeting: The Ohio State University Office of
Research, Gardere, Bio-Rad, Fisher Scientific, Jouan, and Perkin-Elmer.
During the preparation of the workshop and of the manuscript, I received a very
much appreciated help from Sumant Kulkarni, MS and from Leni Moldovan, Ph. D.
This monograph contains contributions from the participants to the workshop. I wish
to thank them all for their attendance, for the high quality of work presented, for their
vivid participation in the debates, and for their willingness to contribute with their
presentation-related materials to this proceedings book.
Nicanor I. Moldovan, Ph. D,
Davis Heart and Lung Research Institute,
Columbus, OH, USA.
CONTENTS
1. CURRENT PRIORITIES IN THE RESEARCH OF CIRCULATING PRE-
ENDOTHELIAL CELLS ..................................................................................... .
Nicanor I. Moldovan
2. IN VIVO AND IN VITRO PROPERTIES OF CD34+ AND CD14+
ENDOTHELIAL CELL PRECURSORS .............................................. 9
Gina C. Schatteman, and Ola A wad
3. EVIDENCE FROM A LEUKEMIA MODEL FOR MAINTENANCE OF
VASCULAR ENDOTHELIUM BY BONE-MARROW-DERIVED
ENDOTHELIAL CELLS ........................................................................ 17
Eberhard Gunsilius
4. CROSS TALK BETWEEN HAEMATOPOIESIS AND
ANGIOGENESIS ..................................................................................... 25
Domenico Ribatti, Angelo Vacca, Beatrice Nico, Enrico Crivellato, Giuseppe De Falco,
and Marco Presta
5. THE CONTRIBUTION OF ADULT HEMATOPOIETIC STEM CELLS
TO RETINAL NEOV ASCULARIZAT ION ......................................... 37
Maria B. Grant, Sergio Caballero, Gary A. J. Brown, Steven M. Guthrie. Robert N.
Mames, Timothy Vaught. and Edward W. Scott
vii
viii CONTENTS
6. IN VITRO TRANSFORMATION OF MONOCYTES AND DENDRITIC
CELLS INTO ENDOTHELIAL LIKE CELLS ................................... 47
Klaus Havemann, Beatriz F. Pujol, and Jiirgen Adamkiewicz
7. PHENOTYPIC OVERLAP BETWEEN MONOCYTES AND
V ASCULAR ENDOTHELIAL CELLS ................................................ 59
Alexander Schmeisser, Christiane Graffy, Werner G. Daniel, and Ruth H. Strasser
8. DISSECTION OF MONOCYTE AND ENDOTHELIAL ACTIVITIES
BY USING VEGF-RECEPTOR SPECIFIC LIGANDS ...................... 75
Matthias Clauss, Frederic Pipp, Katja Issbrucker. Herbert Weich, Matthias Heil, and
Wolfgang Schaper
9. CIRCULATING ENDOTHELIAL CELLS AS A NOVEL MARKER OF
ANGIOGENESIS .................................................................................... 83
Patrizia Mancuso, Angelica Calleri, Cristina Cassi, Alberto Gobbi, Manuela Capillo,
Giancarlo Pruneri, Giovanni Martinelli, and Francesco Bertolini
10. TISSULAR INSEMINATION OF PROGENITOR ENDOTHELIAL
CELLS: THE PROBLEM, AND A SUGGESTED SOLUTION ......... 99
Nicanor I. Moldovan
INDEX .................................................................................................................... 115
NOVEL ANGIOGENIC
MECHANISMS
CURRENT PRIORITIES IN THE RESEARCH OF
CIRCULATING PRE-ENDOTHELIAL CELLS
Nicanor I. Moldovan *
The papers presented at the International Workshop "Novel Angiogenic
Mechanisms" strongly support a role in adult angiogenesis played by circulating cells of
various types, in different settings and circumstances (ischemic limbs, retina, heart, bone
marrow). The main themes that currently dominate this research field are, among others,
the origin of these cells, their phenotypic modulation in vivo and in vitro, their
transformation into endothelial cells (EC) and the mechanisms of their contribution to
neovessels formation. The workshop illustrated the domain's general lines of
investigation and development, for short and medium term. While it is not our intention
to summarize here the contributions of the participants, their opinions are cited below,
when considered appropriate.
1. NATURE AND DESIGNATION OF CPEC
The nature of circulating cells able to engraft and contribute to the maintenance,
repair, or de novo formation of endothelium is still in the process of elucidation (Otani et
al., 2(02). The unsettled terminology reflects both our limited knowledge, and a true
diversity of mechanisms.
Depending on the adopted point of view, stem, progenitor, and precursor were
among the suggested designations of the circulating pre-endothelial cells (CPEC).
However, these terms are not synonymous. Stem cells are capable of self-renewal.
Therefore, those researchers who consider that the CPEC have a true hemangioblast
phenotype, in the embryological sense, consider them as "stem" cells (Grant et al., Chap.
5). Others who see the monocytes or the immature dendritic cells as the potential
initiators of an endothelial phenotype, do not find the notion of stem cells applicable to
their case (Schmeisser et al., Chap. 7), preferring that of progenitor cells, and consider
*Davis Hean and Lung Research Institute. The Ohio State University, Columbus. OH. 43210
Novel Angiogenic Mechanisms: Role ofC irculating Progenitor Endothelial Cells.
Edited by Nicanor I. Moldovan, Kluwer AcademiclPlenum Publishers, 2003. 1
