Stem Cells and Regenerative Medicine: Adult Neurogenesis and Neural Stem Cells, Volume 1

180 Pages·2008·7.07 MB·English

by  Philippe Taupin

S C R
TEM ELLS AND EGENERATIVE
M , V I:
EDICINE OLUME
A N
DULT EUROGENESIS AND
N S C
EURAL TEM ELLS

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S C R
TEM ELLS AND EGENERATIVE
M , V I
EDICINE OLUME
A N
DULT EUROGENESIS AND
N S C
EURAL TEM ELLS

PHILIPPE TAUPIN

Nova Biomedical Books
New York
Copyright © 2008 by Nova Science Publishers, Inc.

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CONTENTS

Preface vii

Introduction xi

Chapter I Neurogenesis in the Adult Central Nervous System 1

Chapter II Adult Neurogenesis in Mammals 21

Chapter III BrdU Immunohistochemistry for Studying Adult Neurogenesis:
Paradigms, Pitfalls,
Limitations and Validation 37

Chapter IV Protocols for Studying Adult Neurogenesis:
Insights and Recent Developments 71

Chapter V Adult Neurogenesis in the Mammalian Central
Nervous System: Functionality and
Potential Clinical Interest 93

Chapter VI Stroke-Induced Neurogenesis:
Physiopathology and Mechanisms 107

Chapter VII Adult Neurogenesis and Neuroplasticity 121

Chapter VIII The Therapeutic Potential of
Adult Neural Stem Cells 133

Conclusion and Perspectives 149

Index 153

PREFACE

The subject of this book is stem cell research and regenerative medicine. Stem cells are
undifferentiated cells that have the ability to differentiate into different lineages of the body.
Stem cells carry tremendous potential for the treatment of a broad range of disease and
injuries. Stem cells exist in embryonic, fetal, and adult tissues, including the adult central
nervous system. This book covers, in depth, the recent developments in stem cell research
and regenerative medicine. Though this book encompasses all the fields of stem cell research
and regenerative medicine, it emphasizes adult neurogenesis and neural stem cell research
and therapy.
Chapter 1 - Contrary to the long-held dogma, neurogenesis occurs throughout adulthood,
and neural stem cells reside in the adult central nervous system (CNS) in mammals. The
developmental process of the brain may thus never end, and the brain may be amenable to
repair. Neurogenesis is modulated in a wide variety of physiological and pathological
conditions, and is involved in processes such as learning and memory and depression.
However, the relative contribution of newly generated neuronal cells to these processes, as
well as to CNS plasticity, remains to be determined. Thus, not does only neurogenesis
contribute to reshaping the adult brain, it will ultimately lead us to redefine our knowledge
and understanding of the nervous system.
Chapter 2 - With the recent confirmation that neurogenesis occurs in the adult brain, and
that neural stem cells reside in the adult central nervous system (CNS), the function of newly
generated neuronal cells in the adult brain is the source of intense research and debate.
Neurogenesis is modulated by a wide variety of physiopathological conditions and
environmental stimuli, offering the possibility that newly generated neuronal cells might be
functionally associated with the response to these processes. Newly generated neuronal cells
in the hippocampus have also been implicated in mechanisms of learning, memory and
depression. However, a number of studies have challenged some of these findings, and the
roles of newly generated neuronal cells in the functioning of the CNS remain to be fully
understood. Neurogenesis has been shown to increase bilaterally in the adult brain and new
neuronal cells are generated at sites of degeneration in the brain during disease and after
injuries. Taken together, these findings suggest that new neuronal cells may be involved in
processes such as homeostasis of brain tissue, regeneration, plasticity, and neuroadaptation.
viii Philippe Taupin
Chapter 3 - Bromodeoxyuridine (BrdU) is a thymidine analog that incorporates DNA of
dividing cells during the S-phase of the cell cycle. As such, BrdU is used for birthdating and
monitoring cell proliferation. BrdU immunohistochemistry has been instrumental for the
study of the development of the nervous system, and to confirm that neurogenesis occurs in
the adult mammalian brain, including in humans. However, the use of BrdU for studying
neurogenesis is not without pitfalls and limitations. BrdU is a toxic and mutagenic substance.
It triggers cell death, the formation of teratomas, alters DNA stability, lengthens the cell
cycle, and has mitogenic, transcriptional and translational effects on cells that incorporate it -
all of which have profound consequences on neurogenesis. BrdU is not a marker of the S-
phase of the cell cycle. As a thymidine analog, it is a marker of DNA synthesis. Therefore
studying neurogenesis with BrdU requires distinguishing cell proliferation and neurogenesis
from other events involving DNA synthesis, like DNA repair, abortive cell cycle re-entry and
gene duplication. BrdU labeling is currently the most used technique for studying adult
neurogenesis in situ. However in many instances, appropriate controls have been overlooked
and events reported as the generation of new neuronal cells in the adult brain misinterpreted,
which makes BrdU labeling one of the most misused techniques in neuroscience.
Chapter 4 - The first evidence that neurogenesis occurs in the adult brain were reported
in rodents in the early 60s, using [3H]-thymidine autoradiography. In the 1980s and 90s, the
advent of new techniques and protocols for studying cell proliferation in situ, and particularly
bromodeoxyuridine-labeling, contributed to confirming that neurogenesis occurs in the adult
brain and neural stem cells reside in the adult central nervous system, including in humans.
Bromodeoxyuridine labeling is currently the method most commonly used for studying
neurogenesis in the adult brain. However, this procedure is not without limitations, and
controversies. In this article, I will review recent protocols for studying adult neurogenesis,
particularly new protocols for studying cell kinetics and cell proliferative history, using
halopyrimidines. I will review these techniques, and discuss their implications for the field of
adult neurogenesis.
Chapter 5 - In the past decades, much evidence has confirmed that neurogenesis occurs
in the adult brain and that neural stem cells reside in the adult central nervous system,
overturning the long-held dogma that we are born with a certain number of nerve cells and
that the brain cannot generate new neurons and renew itself. In the adult brain, neurogenesis
occurs mainly in two areas: the hippocampus and the subventricular zone, and self-renewing,
multipotent neural stem cells have been isolated and characterized in vitro from various
regions of the adult central nervous system. Though significant advances have been made in
this field of research, the identification and function of neural stem cells in the adult central
nervous system remain the source of debate and controversy. Neurogenesis is modulated by
several normal and pathologic conditions, suggesting the involvement of the hippocampus
and the subventricular zone in a broad range of functions, and that environmental stimuli and
pathological conditions may have long-term consequences on the architecture and
functioning of the central nervous system. Neurogenesis is involved in processes such as
learning, memory, and depression, and may also be involved in regenerative attempts after
injuries to the central nervous system. However, the contribution of neurogenesis to these
phenomena remains to be elucidated. Neural stem cells also hold the promise to cure a broad