Table Of ContentRegulation of
Cell Proliferation
and Differentiation
CELLULAR SENESCENCE AND SOMATIC CELL GENETICS
Series editors: Warren W. Nichols Donald G. Murphy
Institute for Medical Research National Institute on Aging
Camden, New Jersey Bethesda, Maryland
Volume 1 REGULATION OF CELL PROLIFERATION AND DIFFERENTIATION
Edited by Warren W. Nichols and Donald G. Murphy
Volume 2 SENESCENCE: DOMINANT OR RECESSIVE IN SOMATIC CELL CROSSES
Edited by Warren W. Nichols and Donald G. Murphy
Regulation of
Cell Proliferation
and Differentiation
Edited by
Warren W. Nichols
Institute for Medical Research
Camden, New Jersey
and
Donald G. Murphy
National Institute on Aging
Bethesda, Maryland
PLENUM PRESS . NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Institute for Medical Research Workshop on Regulation of Cell Proliferation and Dif
ferentiation, Camden, N. J., 1975.
Regulation of cell proliferation and differentiation.
(Cellular senescence and somatic cell genetics; v. 1 )
Includes bibliographical references and index.
1. Cell proliferetion-Congresses. 2. Cell differentiation-Congresses. 3. Cellular
control mechanisms-Congresses. 4. Myogenesis-Congresses. 5. Growth-Congresses.
I. Nichols, Warren W. II. Murphy, Donald G.III. Institute for Medical Research, Cam
den, N. J. IV. Title. V. Series.
QH607.145 1975 ;611'.0181 77-6646
Proceedings of the Institute for Medical Research Workshop on Regulation of
Cell Proliferation and Differentiation held in Camden, New Jersey, May 15-17,1975
©1977 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1977
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
All 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
ISBN-13: 978-1-4615-8848-1 e-ISBN-13: 978-1-4615-8846-7
DOl: 10.1007/978-1-4615-8846-7
Organizing Committee
George M. Martin, Professor of Pathology,
University of Washington School of Medicine,
Seattle, WA
Robert W. Miller, Chief, Epidemiology Branch,
National Cancer Institute, National Institutes
of Health, Bethesda, MD
Donald G. Murphy, Health Scientist Administrator,
National Institute on Aging, National Institutes
of Health, Bethesda, MD
Warren W. Nichols, Head, Dept. of Cytogenetics,
Institute for Medical Research, Camden, NJ
Margery W. Shaw, Director, Medical Genetics Center,
The University of Texas Health Science Center,
Houston, TX
v
Participants
Stephen D. Hauschka, Dept. of Biochemistry,
University of Washington, Seattle, WA
Howard Holtzer, Dept. of Anatomy, University of
Pennsylvania School of Medicine, Philadelphia, PA
Jurgen Herrmann, Clinical Genetics Center, University of
Wisconsin, Madison, WI
Irwin R. Konigsberg, Dept. of Biology, University of
Virginia, Charlottesville, VA
Mark Nameroff, Dept. of Biologic Structure,
University of Washington School of Medicine, Seattle, WA
John M. Opitz, Clinical Genetics Center, University of
Wisconsin, Madison, WI
David W. Smith, Dysmorphology Unit, Dept. of Pediatrics,
University of Washington School of Medicine, Seattle, WA
Richard C. Strohman, Dept. of Zoology, University of
California, Berkeley, CA
Frank E. Stockdale, Stanford University School of
Medicine, Stanford, CA
vi
Preface
In 1974 The National Institute on Aging established a
somatic cell genetic resource for aging research at the Institute
for Medical Research in Camden, New Jersey. Within this program
there is a yearly workshop to promote theory and concept develop
ment in aging research with the specific purpose of addressing
the use of genetically marked cells for aging research and to
stimulate interest in aging research by workers in a variety of
disciplines. This monograph, The Regulation of Cell Proliferation
and Differentiation, is the result of the first workshop held
May 15-17, 1975. The concept of the workshop was to consider two
main areas: First, a discussion of clinical syndromes expressing
as a major manifestation excessive growth, deficient growth or
failure to thrive; and second, to present work in cellular and
molecular biology on a model system suitable for in vitro study of
regulation of cell proliferation and diff2rentiation. The model
selected for this was skeletal muscle.
It has been widely accepted that normal somatic cells from
individual human donors display limited replicative lifespans when
cultivated in vitro (1,2). That such "clonal senescence" may be
related to in vivo aging is suggested by observations relating the
replicative lifespans of cultures to donor age (3-5,13) donor
genotype (4-7) and donor's tissue of origin (5,8).
A variety of theories have been developed to explain in vitro
clonal senescence (9). One such theory attributes the loss of
replicative potential to a type of terminal differentiation (10-12)
analogous to what occurs in vivo in such cell lineages as the
hematopoietic system. By this view, cultures are largely estab-
lished by stern cells which segregate specialized post-replicative
cells. Ultimately, such cultures may "differentiate themselves
to death." According to this formation, it would seem reasonable
to predict that the maintenance of function in various tissues
capable of cell turnover would be related to such parameters as
size of stern cell pool, rates of depletion of stern cells, time of
onset of differentiation, and longevity of terminally differentiated
cells. It is also obvious that these parameters would be of
vii
viii PREFACE
critical importance in the determination of rates of growth and
of ultimate tissue mass. Thus, clinical disorders of excessive
growth, deficient growth and aberrant differentiation would be
of interest as sources of material for the investigation of cell
proliferation and differentiation in cell culture. To date,
most studies on in vitro clonal senescence have utilized skin
"fibroblasts" and the majority of banked lines are of this type.
The in vivo parental origin of these cells is unknown, as is the
nature of the putatively terminally differentiated progeny. A
major goal of this conference is to encourage the exploration of
other cell culture systems for studies on cell aging. We have
chosen to concentrate on the skeletal muscle model, largely
because of recent progress in the cellular and molecular biology
of the system, progress which is well documented in the present
conference. Let us hope that the many talented biologists
utilizing that model will ultimately elucidate the mechanisms by
means of which a mammalian genome regulates and couples cell
proliferation and differentiation. Although the publication of
this first work was unavoidably delayed, the authors have reviewed
and updated their manuscripts so that they represent 1977
concepts and thoughts.
George M. Martin
Robert W. Miller
Donald G. Murphy
Warren W. Nichols
Margery Shaw
PREFACE ix
REFERENCES
1. Hayflick, L. and Moorhead, P.S. The serial cultivation of
human diploid cell strains. Exp. Cell Res. 25:585, 1961.
2. Hayflick, L. Biology of human aging. Amer. J. Med. Sci.
265:432, 1973.
3. Hayflick, L. The limited in vitro lifetime of human diploid
cell strains. Exp. Cell Res. 37:614, 1965.
4. Goldstein, S., Littlefield, J.W. and Soeldner, J.S. Diabetes
mellitus and aging. Diminished plating efficiency of culti
vated human fibroblasts. Proc. Nat. Acad. Sci. USA 64:155,
1969.
5. Martin, G.M., Sprague, C.A. and Epstein, C.J. Replicative
lifespan of cultivated human cells. Effects of donor's age,
tissue and genotype. Lab. Invest. 23:86, 1970.
6. Goldstein, S. Lifespan cultured cells in progeria. Lancet 1:
424, 1969.
7. Vracko, R. and Benditt, E.P. Restricted replicative life-span
of diabetic fibroblasts in vitro: its relation to microangio
pathy. Fed. Proc. 34:68, 1975.
8. Martin, G.M. and Sprague, C.A. Symposium on in vitro studies
related to atherogenesis. Life histories of hyperplastoid
cell lines from aorta and skin. Exp. Mol. Path. 18:125, 1973.
9. Orgel, L.E. Ageing of clones of mammalian cells. Nature 243:
441, 1973.
10. Cristofalo, V.J. Animal cell cultures as a model system for
the study of aging. Adv. Geront. 4:45, 1972.
11. Martin, G.M., Sprague, C.A., Norwood, T.H. and Pendergrass,
W.R. Clonal selection, attenuation and differentiation in an
in vitro model of hyperplasia. Amer. J. Path. 74:137, 1974.
12. Martin, G.M., Sprague, C.A., Norwood, T.H., Pendergrass, W.R.,
Bornstein, P., Hoehn, H. and Arend, W.P. Do hyperplastoid
cell lines "differentiate themselves to death"? in Impairment
of Cellular Functions During Aging in vivo and in vitro, ed.
V.J. Cristofalo and E. Holeckova. Plenum Press, N.Y., 1975.
13. Schneider, E.L. and Mitsui, Y. Relationship between in vitro
cellular aging and in vivo human age. Proc. Nat. Acad. Sci. 73:
3584, 1976.
Contents
CLINICAL OVERGROWTH. UNDERGROliTH. AND FAILURE TO THRIVE
Dysplasia. Malformations and Cancer, Especially
with Respect to the Wiedemann-Beckwith Syndrome
Jurgen HerPmann~ Enid F. Gilbert and
John M. Opitz. . . . • . . . . . . • . 1
Delayed Mutation as a Cause of Genetic Disease in Man:
Achondroplasia and the Wiedemann-Beckwith Syndrome
Jurgen HePPmann and John M. Opitz . . . . . . . . 65
Undergrowth Disorders
David W. Smith. 81
CELLULAR REGULATION IN CELL PROLIFERATION IN VITRO
A Review of Controversial Issues in Myogenesis
HOwaPd HoZtzer, G. Yeoh, N. Rubinstein,
s.
J. Chi, FeZlini and S. Dienstman . • • 87
The Culture Environment and its Control of Myogenesis
Irwin R. Konigsberg . .. . . . . . . . . . 105
Fusion. Phospholipase C, and Myogenesis
Mark Nameroff. . . . . . . . . . 139
MOLECULAR STUDIES IN REGULATION OF CELL PROLIFERATION
Application of Clonal Assay Methods to the Analysis
of Tissue Development and Diseased States
Stephen D. Hauschka . • . . . • . . . . • . • 143
xi
