Live links to the resources are available in the actual article,
accessable at the end of this post.
Stem Cells: The Promises and Pitfalls
Richard S Nowakowski Ph.D and Nancy L Hayes
Department of Neuroscience and Cell Biology UMDNJ-Robert Wood Johnson
Medical Center Piscataway, NJ 08854
Correspondence: Dr Richard S Nowakowski, Department of Neuroscience
and Cell Biology, UMDNJ-Robert Wood Johnson Medical Center, 675 Hoes
Lane, Piscataway, NJ 08854. Tel.: (732) 235-4981, Fax: (732) 235-
4029, E-mail: rsn@umdnj.edu
Stem cells have reached the pinnacle of scientific acceptance, i.e.
they are a "hot topic" in the newspapers and on television talk
shows. Even the President of the United States recently devoted an
address to the nation on a major policy related to this topic. The
reason for the interest is clear; stem cells are believed to provide
a tool by which new tissues and organs can be made and by which old
ones can be repaired. For the central nervous system (CNS) and other
organs, e.g. cardiac muscle, this is potentially of crucial
importance because cells lost due to damage from injury or disease
are not normally replaced. In the brain, the result is permanent
neurological or psychiatric signs or symptoms that depend on the area
(s) damaged. The hope and the promise is that stem cells and, in
particular, neural stem cells will be capable of repairing and/or
replacing the neurons lost to trauma, disease or abnormal aging. The
promises are, however, accompanied by pitfalls (Nowakowski and Hayes
2000). Here we discuss four pitfalls, three conceptual and one
technical, that need to be considered as the literature in this field
expands.
PITFALL #1:PROLIFERATION AND "STEMNESS"ARE NOT EQUIVALENT
The first issue that must be addressed, of course, is identity: what
are stem cells and what are neural stem cells? Stem cells have been
defined as "clonogenic, self-renewing progenitor cells that can
generate one or more specialized cell types" (Anderson et al. 2001).
This means that they are proliferating cells that can produce one or
more different types of progeny AND, importantly, can produce more
cells like themselves, a property that is generally referred to
as "self-renewal.
significant contrast to the properties of other progenitor cells,
precursor cells, transit amplifying cells and other types of
proliferating cells that have been identified by various authors.
These other kinds of proliferating cells all are generally said to
have limited potential. However, although it is clear that all
proliferating cells are not equivalent, the varying potential
(or "stemness") of different types of proliferating cells is open for
debate (Blau et al. 2001). In the CNS, neural stem cells are
generally considered to be proliferating cells that can produce
neurons, glia, progenitor cells, and also more neural stem cells,
whereas progenitor cells are generally considered to be more limited
in their potential and can produce only one cell type, e.g.
oligodendrocytes. The lesson from this pitfall is simple: a
proliferating cell is not necessarily a stem cell.
PITFALL #2: IN VITRO IS NOT THE SAME AS IN VIVO
Because there are no clear-cut markers for stem cells, the
identification of a cell as a stem cell is generally achieved
retrospectively through an examination of its progeny. This
identification process is more easily achieved in vitro (Anderson et
al. 2001) than in vivo because only in vitro can one be sure that one
is not only following the progeny of a single cell but also that one
accounts for all of the progeny. In addition, the in vitro
environment is more controlled and provides opportunities for
multiple observations through time of the same cells, while in vivo
experiments allow only a single temporal picture of any stem cell and
its progeny. However, to reach an understanding of the complex issue
of neural stem cells, it is necessary to identify them in vivo and
also to define their potential in vivo. In part, this is necessary
because of the possibility that the mere act of putting cells in
vitro may affect their proliferative (and other) characteristics
(Sherr and DePinho 2000); more directly, it is necessary because
therapeutic advances will require in vivo manipulations. The
difficult questions related to neural stem cells in vivo are tackled
by three articles in this issue. All three deal with various aspects
of the behavior of stem cells. Taken together, these articles review
the field broadly, covering: (1) the role of neural stem cells during
the developmental period and also during the complex tissue
reorganization that is generally referred to as plasticity (Vaccarino
et al. 2001); (2) the intriguing idea that there exist neural stem
cells in the neocortex that can be coaxed to become neurons (Magavi
and Macklis 2001); (3) the idea that one population of proliferating
cells in the adult brain, i.e. those in the dentate gyrus, may be
involved in depression and stress and that neurogenesis in the
dentate gyrus can be influenced by antidepressant therapies (Duman et
al. 2001). Each of these papers reflects the current state of the art
of one specific area in this rapidly growing field, and each takes a
different approach toward illuminating the roles, properties and
potentials of stem cells in vivo.
PITFALL #3: RULES DURING DEVELOPMENT AND RULES IN THE ADULT MAY DIFFER
Vaccarino (Vaccarino et al. 2001) points out that the mechanisms
operating to control stem cell proliferation during development are
likely to be "re-used" in the adult animal. This is a reasonable
working hypothesis, and Vaccarino details some of the molecular
controls on this proliferative population. What, exactly, are the
cellular behaviors that these molecular controls are controlling?
During development, the role of neural stem cells is to build the
diverse components of the nervous system. This occurs in an orderly
and coordinated fashion, so that the right numbers and classes of
cells are produced in a precise sequence. At the earliest stages
after the formation of the neural tube, the proliferating cells of
the CNS line the ventricles forming a proliferative zone called the
ventricular zone. The proliferating cells themselves form a
pseudostratified ventricular epithelium (or PVE) that is relatively
uniform in its histological appearance regardless of its location in
the neuraxis and relatively unchanging as a function of developmental
time. From this seemingly uniform population of proliferating cells
the diversity of the nervous system develops through differential
gene expression that defines segmental (e.g. spinal cord, brain stem,
telencephalon)
radial (e.g. layers and laminae) specializations in form and
function. The best studied portion of this extensive proliferative
population are those cells that produce the neocortex. For the
neocortical PVE we know for example that in mouse from the time of
production of the first neuron until the end of neocortical
neuronogenesis there are 11 cell cycles during a 6-day period. At the
end of this period, the PVE involutes, and the proliferating cells
disappear. During development the length of the cell cycle changes,
and the proportion of cells that re-enter (P cells) versus leave (Q
cells) the cell cycle also changes (Takahashi et al. 1996). This
seems to be accomplished by a cycle-by-cycle adjustment of the
proportions of the three possible types of cell division, symmetric
non-terminal (2 P cells), symmetric terminal (2 Q cells) and
asymmetric (1 P cell and 1 Q cell). As a result, the dynamic changes
expected and appropriate for a developing organ occur, i.e. during an
early expansion phase there are more P cells produced than Q cells,
and the brain continues to expand as new neurons are produced, and
during a late extinction phase, there are more Q cells produced than
P cells as the proliferative population involutes. The result is a
brain that grows during the expansion phase and continues to produce
neurons until the proliferative population is extinguished.
Interestingly, calculations made from measurements of P and Q yield a
growth rate for the brain and the production of a number of neurons
that agrees quite well with the actual facts (Caviness et al. 1995;
Takahashi et al. 2001). As detailed by Vaccarino (Vaccarino et al.
2001), growth factors and other small molecules, including FG2 (Ghosh
and Greenberg 1995; Vaccarino et al. 1999a; 1999b; Raballo et al.
2000), PACAP (Nicot and DiCicco-Bloom 2001; Suh et al. 2001), IGF-1
(Drago et al. 1991), NT3 (Ghosh and Greenberg 1995) may all play a
role either as a mitogen or an anti-mitogen. In addition,
proliferating cells in the ventricular zone are interconnected by gap
junctions (Bittman et al. 1997; Bittman and LoTurco 1999) and express
GABA(A) receptors, indicating (Owens et al. 1999) that cell-cell
signaling (Owens et al. 2000) may also play a role in regulating the
dynamic behaviors and Q/P decisions of the proliferating cells of the
ventricular zone, although it remains to be determined how these
molecules interact with the cell cycle machinery of the proliferating
cells (Dyer and Cepko 2001).
The proliferative population of the developing brain may not,
however, completely disappear at the end of the developmental period.
Two clear examples of continued cell proliferation throughout
adulthood have been well documented. The first of these is in the
anterior part of the subventricular zone and the rostral migratory
stream, where extensive proliferation produces neurons (and glia) for
the olfactory bulb (Luskin 1993; Doetsch et al. 1999). The second
well understood example is in the dentate gyrus, where a
proliferative zone in the hilus produces neurons and glia (Gage et
al. 1998); this second population is the topic of the paper by Duman
et al. in this issue (Duman et al. 2001). A third population of stem
cells has been suggested to reside in the substance of the brain
itself in the form of cells with astrocyte-like properties (Laywell
et al. 2000). The existence of this population is part of the
analysis of Magavi and Macklis (Magavi and Macklis 2001). How do
these adult stem cell populations behave and how are they regulated?
Are the rules unique to adult stem cells or, as suggested by
Vaccarino (Vaccarino et al. 2001), do the mechanisms from development
apply? In one clear way, the adult stem cells are distinctly
different from the PVE of the embryo in that they do not form a
distinct epithelium with interkinetic nuclear movements. They are
instead more similar to the proliferating cells of the secondary
proliferative population found in the subventricular zone of the
embryo. In addition, one might speculate that the adult neural stem
cells, rather than following an orderly sequence of events to produce
specific products at specific times, respond instead to local
environmental influences to produce an output appropriate for the
conditions. The experiments of both Duman (Duman et al. 2001) and
Magavi and Macklis (Magavi and Macklis 2001) are oriented toward this
possibility. However, at this stage we do not know if the various
neural stem cell populations that exist in the adult animal have
uniform or disparate potential (i.e. Pitfall #1). The best studied of
these populations is the one that resides in the dentate gyrus, and
that is the topic of the Duman et al. contribution, so let's examine
this population a bit more carefully.
In the case of the dentate gyrus, a relatively small number of
proliferating cells reside in the hilus. This population is derived
from the proliferating cells of the hippocampal PVE during embryonic
stages (Nowakowski and Rakic 1981), and in the rodent this population
becomes firmly established around the time of birth. During the early
postnatal period in rodents, this intrahilar proliferative population
produces about 80% of the cells of the granule layer of the dentate
gyrus (Bayer and Altman 1975), but these events occur prenatally in
monkeys and humans, reversing the proportions to 80% prenatal and 20%
in the early postnatal period (Nowakowski and Rakic 1981).
Interestingly, during the early postnatal period, proliferation and
survival of the output from this population are significantly
affected by NMDA-related agonists and antagonists (Gould et al. 1994)
suggesting that experience mediated by axonal inputs might affect
neuron production during this period. In the adult dentate gyrus, the
population of proliferating cells is small compared with the size of
the total population of neurons. However, the numbers of
proliferating cells and the numbers of neurons they produce varies
even within a single species (Boss et al. 1985; Kempermann et al.
1997). In monkey, the number of proliferating cells is about the same
as in the rat, but due to the larger size of the monkey dentate gyrus
they comprise a much smaller proportion of the total population
(Kornack and Rakic 1999). The output from this population consists of
neurons, glia, cells with an unknown phenotype (Kempermann et al.
1997, 1998a, 1998b), and cells that die (Hayes and Nowakowski,
unpublished observations)
granule cells (Crespo et al. 1986) and seem to grow mossy fibers
(Stanfield and Trice 1988) and to become integrated into the
circuitry of the brain (Markakis and Gage 1999). The output is also
apparently stable enough to affect an increase in the volume of the
dentate gyrus over the course of several months (Bayer 1982). This
proliferation seems to persist for the lifetime of the animal,
although there is some reduction at later ages (Kempermann et al.
1998a). The paper by Duman et al. (2001) in this issue extends the
work of others and shows that the output of this proliferative
population, i.e. "neurogenesis"
cells can be affected by pharmacological and other manipulations
including behavioral experience (Kempermann et al. 1998b). How this
proliferation is maintained and variability in output is achieved are
unclear because precise measures of the behavior of this
proliferative population have not yet been made, although we now know
that the cell cycle in rat is about 25 h (Cameron and McKay 2001).
The simplest way to imagine this maintenance is to assume that the
proliferating population in the adult dentate gyrus is a homogeneous
population growing at approximately "steady-state"
or no net change in the size of the proliferating population with
each pass through the cell cycle. The simplest such proliferating
population would consist entirely of cells that divide
asymmetrically, i.e. with each pass through the cell cycle one
daughter cell re-enters the S-phase and remains a proliferative (or
P) cell, and the other daughter cell exits the cell cycle to become a
post-mitotic (or Q) cell (Figure 1), left panel), i.e. the Q cells
comprise the output (including neurons) from the proliferative
population. If the dentate gyrus proliferative population were of
this type, then each proliferative cell in the dentate gyrus would
have exactly the same behavior, at least with respect to the fates of
the two daughters that are produced at each cell cycle. Variable
output (such as that demonstrated by Duman et al. 2001) from a
population with these properties could only be achieved by affecting
the survival of the Q cells. For this type of population, the number
of P cells would be invariable because the population can divide only
asymmetrically. In Figure 1, panels B-E, an alternative form of
steady-state growth is presented. Here the proliferative fates of the
two daughter cells are not correlated (i.e. during early G1, each
daughter cell interacts independently with the environment to make
its decision to exit the cell cycle or not), and all three types of
cell divisions occur. However, because P = Q = 0.5 the mixture of
cell divisions at each cell cycle is 1:2:1 and both the size of the
proliferative population and the output are constant over the
lifespan of the proliferative population. For this alternative form
of steady-state growth, variable output (such as that demonstrated by
Duman et al. 2001) could be achieved by slight changes in P and Q
from the steady-state value of 0.5; this would change the mixture of
cell divisions from 1:2:1 and simultaneously affect the size of both
the proliferative population and the output from the proliferative
population. Thus, the more complex populations schematized on the
right side of Figure 1 are possibly more responsive to the sorts of
manipulations (e..g, anti-depressants and others as reviewed by Duman
et al. 2001) that affect the production of the neurons in the adult
dentate gyrus. At this time, there is insufficient data to evaluate
whether either of these possible models (or perhaps some other one)
reflects the situation in the living animal. Note that, in either
case, in order to persist for the lifetime of the animal, the
lifespan of the lineages as shown in Figure 1 must correspond to the
lifetime of the animal. In addition, in either case, the situation is
dramatically different from what happens during development, where
the proportions of cell divisions change dramatically as development
proceeds (Takahashi et al. 1996), thereby limiting the lifespan of
the proliferative population.
Figure 1
Two populations undergoing steady-state growth. At every cell cycle,
both have a constant number of proliferative cells (P) and both
produce the same number of post-proliferative cells (Q), i.e. at each
generation P = Q = 0.5. In the population on the left, all cells have
the same lineage in which each proliferating cell divides
asymmetrically. In the population on the right, the lineages would
vary. Here an initial population of four cells (B-E) beget daughters
and granddaughters that are assigned a P/Q fate randomly. If the
overall population is a mixture (1:2:1) of all three possible types
of cell division, then the number of proliferating cells and the
output of this population are the same as that shown in A at every
generation.
PITFALL #4: TECHNICAL LIMITATIONS OF BROMODEOXYURIDINE (BRDU) LABELING
The issue of how this adult proliferative population is regulated is
addressed by Duman et al. (Duman et al. 2001). They show that various
anti-depressant treatments increase the numbers of cells per dentate
gyrus that can be labeled by BrdU. These are interesting and
important findings for they indicate that changes in the
proliferating population in the dentate gyrus are correlated with
depression and possibly also are affected by the drugs used to treat
depression. This raises the issue of how these drugs affect the
possible lineages that are shown in Figure 1 asking (but not yet
answering) what is the cellular effect of these anti-depressants vis-
a-vis the proliferative process. In addition, these studies and also
those of Magavi and Macklis (in this issue) also point out the
dependence of this field on BrdU for assessing "neurogenesis.
dependence on this single method is an important consideration.
BrdU labeling was introduced as a tool for studying cell
proliferation in the developing nervous system (Nowakowski et al.
1989); it is unclear how well that tool functions in adult animals.
As an analog of thymidine, BrdU is a marker for DNA synthesis and not
necessarily a marker for cell proliferation. There are several
consequences of this basic fact. First, BrdU labels only cells that
are synthesizing DNA; thus, a single injection of BrdU will label
cells in the S-phase (Nowakowski et al. 1989), and the S-phase is a
small proportion of the whole cell cycle (Nowakowski et al. 1989;
Takahashi et al. 1995). It must be considered that relative changes
in the length of the S-phase with respect to the total length of the
cell cycle could result in the appearance of more labeled cells with
a given paradigm. For example, an increase in the length of the S-
phase by 25% with no change in either the length of the whole cell
cycle or the actual number of proliferating cells will yield an
apparent increase in the number of BrdU labeled cells by 25%. Thus,
although it is clear that the various treatments have some effect on
proliferation in the adult dentate gyrus, it is not clear exactly
what this effect is. Specifically, it is not determined if these
experiments have measured actual changes in the numbers of
proliferating cells, or if changes in cell cycle parameters account
for the measured differences in the number of labeled cells. Analysis
of the cell cycle is necessary to evaluate the results of such
experiments and to determine which of several possible
interpretations is correct. Second, BrdU can label non-proliferating
cells if they are synthesizing DNA. Thus, under some circumstances,
for example the massive lesions exploited by Magavi and Macklis
(Magavi and Macklis 2001), it is essential to determine if the
observed BrdU incorporation is associated with: (1) DNA replication
and cell proliferation or (2), with other conditions during which DNA
is known to be synthesized in cells, i.e. DNA repair (Selden et al.
1993), apoptosis (Katchanov et al. 2001) or (3) with the development
of tetraploidy (Yang et al. 2001). The experiments of Magavi and
Macklis (Magavi and Macklis 2001) interpreted BrdU labeling as
indication that "new neurons" have been made, but the pathology
induced by the lesion could cause DNA synthesis to occur in "old
neurons." For example, perhaps in a small percentage of the injured
cells DNA repair is successful, and the neurons do not die. This
possibility is perhaps reinforced by the recent finding that neurons
in areas affected by Alzheimer's disease become tetraploid prior to
cell death and remain in this state for an extended period of time
(Yang et al. 2001); it is plausible that injury such as that produced
by Magavi and Macklis (Magavi and Macklis 2001) could produce a
similar phenomenon. One simple criterion for differentiating between
replication and other causes of BrdU incorporation is to demonstrate
the existence of a appropriate number of BrdU labeled mitotic figures
that would appear as the cells labeled in S phase pass through G2 and
enter M (Nowakowski and Hayes 2000). Labeled mitotic figures in
appropriate numbers would confirm that the increased BrdU
incorporation is associated with proliferation and would not appear
in a population undergoing DNA repair or with DNA replication in
cells becoming tetraploid.
THE FUTURE
The promises of stem cells for CNS repair and treatment of mental
illnesses are profound and cause for enthusiasm among all
neuroscientists. The enthusiasm, however, should not blind us to the
need for prudence and the rigorous use of the scientific method. The
pitfalls described above are all experimentally addressable. Thus,
they should be used to guide both our conceptual framework and, more
importantly, the design of future studies which incorporate the
necessary additional experiments. It is essential to explore and
eliminate plausible alternative explanations for continued advances
in this field to occur.
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http://www.nature.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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