Integrating Physiological Regulation
with Stem Cell and Tissue Homeostasis
Daisuke Nakada,1Boaz P. Levi,1and Sean J. Morrison1,*
1Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University
of Michigan, Ann Arbor, MI 48109-2216, USA
Stem cells are uniquely able to self-renew, to undergo multilineage differentiation, and to persist throughout
life in a number of tissues. Stem cells are regulated by a combination of shared and tissue-specific mecha-
nisms and are distinguished from restricted progenitors by differences in transcriptional and epigenetic
regulation. Emerging evidence suggests that other aspects of cellular physiology, including mitosis, signal
transduction, and metabolic regulation, also differ between stem cells and their progeny. These differences
may allow stem cells to be regulated independently of differentiated cells in response to circadian rhythms,
changesin metabolism, diet, exercise, mating, aging,infection, and disease. This allowsstem cells to sustain
homeostasis or to remodel relevant tissues in response to physiological change. Stem cells are therefore not
only regulated by short-rangesignalsthat maintain homeostasis within their tissue of origin, but also by long-
range signals that integrate stem cell function with systemic physiology.
Stem cells are critical for the development and maintenance of
tissues. The zygote gives rise to pluripotent cells in the embryo,
and thenthese cells give rise to multipotent, tissue-specific stem
cells that complete the process of organogenesis during fetal
development. In a number of tissues, including the nervous
and hematopoietic systems, tissue-specific stem cells persist
throughout life to regenerate cells that are lost to turnover, injury,
and disease. Self-renewing divisions, in which stem cells divide
to make more stem cells, allow stem cell pools to expand during
fetal development and then to persist throughout adult life. The
capacity to remain undifferentiated and to self-renew throughout
life distinguishes stem cells from other cells.
Stem cells are required for the maintenance and function of
a number of adult tissues. In the central nervous system (CNS),
stem cells persist throughout life in the forebrain lateral ventricle
subventricular zone, as well as in the subgranular zone of the
hippocampal dentate gyrus (Zhao et al., 2008). Stem cells in
both regions of the adult brain give rise to new interneurons
that regulate the ability to discriminate new odors or certain
forms of spatial learning and memory, respectively (Alonso
et al., 2006; Gheusi et al., 2000; Zhang et al., 2008). Hematopoi-
etic stem cells (HSCs) give rise to blood and immune system
cells throughout life, and HSC depletion leads to immunocom-
promisation and hematopoietic failure (Park et al., 2003; van
der Lugt et al., 1994). Stem cells also persist throughout life in
numerous other tissues, including the intestinal epithelium
(Barker et al., 2007).
Stemcells differ fromrestricted progenitors as aconsequence
upon transcriptional and epigenetic regulators that are not
required by restricted progenitors or differentiated cells in the
same tissues (He et al., 2009). The environment also regulates
stem cell function as specialized niches regulate stem cell main-
tenance throughout life using strategies that are often shared
across species and tissues (Fuller and Spradling, 2007; Morrison
and Spradling, 2008; Scadden, 2006).
Physiological homeostasis requires regulation at many levels,
from the molecular level within cells to the cellular level within
homeostasis in organisms is regulated by differentiated cells
(e.g., pancreatic b cells that sense changes in glucose and
secrete insulin, neurons that sense environmental inputs and
modulate physiological and behavioral responses, etc.). Stem
cells contribute to homeostasis partly by generating and regen-
erating appropriate numbers of differentiated cells. However,
stem cell function itself must also be modulated in response to
physiological changes to remodel tissues to keep pace with
changing physiological demands (Drummond-Barbosa and
Spradling, 2001; Hsu and Drummond-Barbosa, 2009; McLeod
et al., 2010; Pardal et al., 2007).
Data increasingly suggest that many aspects of cellular phys-
iology differ between stem cells and their progeny. At least some
aspects of metabolic regulation differ between stem cells and
restricted progenitors. This is interesting because most of what
we know about metabolic pathways comes from studies of cell
lines and nondividing differentiated cells (such as liver and
muscle). As a result, it remains unclear whether most aspects
of metabolism are regulated similarly in all dividing somatic cells
or whether different kinds of dividing somatic cells employ
different metabolic mechanisms. If systemic physiological
homeostasis depends upon the concerted regulation of stem
cell functioninmultiple tissues,thenstemcellsmay havedistinct
metabolic mechanisms that allow them to respond to these
In this review we will discuss mechanisms by which stem cells
respond to physiological changes such as feeding, circadian
rhythms, exercise, and mating. One of the key challenges for
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
the next ten years will be to understand how stem cell regulation
is integrated with the physiology of whole organisms to maintain
The Importance of Executive Control
by Transcriptional Networks
Embryonic stem (ES) cells are derived from the inner cell mass of
the blastocyst prior to implantation. They are pluripotent and
have indefinite self-renewal potential. These features of ES cells
are regulated by a unique transcriptional network involving Oct4,
Sox2, and Nanog (Jaenisch and Young, 2008). These transcrip-
tion factors form a core autoregulatory network that maintains
pluripotency by inducing genes that promote self-renewal and
by repressing genes that drive lineage restriction. Other epige-
netic (Jaenisch and Young, 2008), transcriptional (Dejosez
et al., 2008), and signaling (Ying et al., 2008) regulators collabo-
rate with this network to sustain the pluripotent state. Although
the cell cycle (reviewed in He et al., 2009) and some aspects of
metabolism (Wang et al., 2009) are also regulated differently in
pluripotent stem cells as compared to other cells, it remains
unclear how pervasive the differences in cellular physiology
are, relative to other cells.
a pluripotent state by ectopically expressing a small number of
pluripotency-associated transcription factors argues that all
differences between pluripotent stem cells and other cells can
be determined by this transcriptional network. Pluripotency
can be induced in differentiated mouse and human cells by
expressing Oct4 along with various combinations of other tran-
scription factors (Park et al., 2008; Stadtfeld and Hochedlinger,
2010; Takahashi et al., 2007; Takahashi and Yamanaka, 2006;
Yu et al., 2007). These induced pluripotent stem (iPS) cells
resemble ES cells in terms of gene expression, cell-cycle regula-
tion, teratoma formation, and metabolic regulation (Prigione
et al., 2010; Stadtfeld and Hochedlinger, 2010). Importantly,
mouse iPS cells have the ability to generate a viable adult mouse
upon injection into blastocysts (Boland et al., 2009; Zhao et al.,
2009). This means that all of the aspects of cellular physiology
that are necessary for pluripotent cells to differentiate into
normal specialized cells can be induced by these transcription
On the other hand, recent studies have identified epigenetic
aberrations in iPS cells that indicate that these cells are often
not fully reprogrammed to a normal pluripotent state (Kim
et al., 2010; Lister et al., 2011). This raises the questions of
whether some differences in cellular physiology, or at least
epigenetic state, are regulated independently of the transcrip-
tional network and whether these differences might stabilize
the pluripotent state.
Stem Cell Self-Renewal Is Different
from Restricted Progenitor Proliferation
Tissue-specific stem cells depend on transcription factors that
regulate stem cell self-renewal but not restricted progenitor
proliferation. The Sox17 transcription factor is required for the
maintenance of fetal and neonatal HSCs but is not expressed
by the vast majority of restricted progenitors in the hematopoi-
etic system (Kim et al., 2007). Sox17 is not expressed by neural
stem cells, but other Sox family transcription factors likely
perform similar functions in neural stem cells. Sox2 and Sox9
are required by CNS stem cells during fetal development, as
well as in the adult brain (Avilion et al., 2003; Favaro et al.,
2009; Graham et al., 2003; Scott et al., 2010). Sox10 is required
to maintain neural crest stem cells during peripheral nervous
system (PNS) development but is not required by the restricted
neuronal progenitors that arise from these cells (Kim et al.,
2003). Different Sox family members are therefore required to
maintain undifferentiated stem cells in different tissues during
Prdm family transcription factors are also required by stem
cells in multiple tissues. Prdm14 is required by primordial germ
cells and stabilizes ES pluripotency (Chia et al., 2010; Yamaji
et al., 2008). Prdm1/Blimp1 is required for primordial germ cells
and progenitors in the sebaceous gland (Horsley et al., 2006;
Ohinata et al., 2005). Prdm16 is required by stem cells in the
hematopoietic and nervous systems, but not by most restricted
progenitors in the same tissues (Chuikov et al., 2010). Key tran-
scription factors, or transcription factor families, therefore
sarily promoting the proliferation of restricted progenitors in the
same tissues (Figure 1A).
Transcription factors collaborate with epigenetic regulators to
maintain undifferentiated stem cells. The polycomb family chro-
matin regulator, Bmi-1, is required for the maintenance of post-
natal stem cells in multiple tissues, including the hematopoietic
and nervous systems, but not for the proliferation of most
restricted progenitors in the same tissues (Lessard and Sauva-
geau, 2003;Molofsky etal., 2003;Park et al.,2003). The trithorax
protein Mll is required for the maintenance of HSCs, but not for
the proliferation of restricted myeloid and lymphoid progenitors
(Jude et al., 2007; McMahon et al., 2007). Mll is also required
for neurogenesis by CNS stem cells, but not for gliogenesis
(Lim et al., 2009). Differences between stem cell self-renewal
and restricted progenitor proliferation are not absolute, as
some restricted progenitors, such as lymphoid progenitors and
proliferation (Leung et al., 2004; van der Lugt et al., 1994). None-
theless, these transcriptional and epigenetic mechanisms do not
generically regulate the proliferation of all cells, even when the
mechanisms are widely conserved among stem cells in multiple
Cell-cycle regulation also distinguishes stem cells from
restricted progenitors in the same tissues. In some adult tissues,
the stem cells are quiescent most of the time, whereas most
restricted progenitors divide more frequently. A good example
is the hematopoietic system, wherein only a few percent of
HSCs are in cycle at any one time (Kiel et al., 2007) and a subset
of HSCs divide only once every few months (Foudi et al., 2009;
Wilson et al., 2008). Although most restricted hematopoietic
progenitors divide much more frequently, there are some
progenitors (Pelayo et al., 2006), that can reversibly enter and
exit the cell cycle over long periods of time, much like HSCs.
As a consequence, bromo-deoxyuridine label retention is not
a sensitive or specific marker of HSCs (Kiel et al., 2007) but
can be used in concert with other HSC markers to identify
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
aslowly dividing subset of HSCs (Foudi etal., 2009; Wilson et al.,
2008). There is also evidence that some adult neural stem cells
(Doetsch et al., 1999; Morshead et al., 1994; Pastrana et al.,
2009) and hair follicle stem cells (Blanpain et al., 2004; Cotsarelis
et al., 1990; Tumbar et al., 2004) are quiescent much of the time.
However, quiescence is not a defining feature of stem cells,
because stem cells in each of these tissues divide rapidly during
fetal development (Lechler and Fuchs, 2005; Morrison et al.,
1995; Takahashi et al., 1995) and can be reversibly recruited
into cycle, such as after tissue injury (Doetsch et al., 1999;
Harrison and Lerner, 1991; Kobielak et al., 2007; Lugert et al.,
2010). Moreover, stem cells in the intestinal epithelium divide
every day (Barker et al., 2007), demonstrating that even faculta-
tive quiescence is not an obligate feature of adult stem cells.
cell-cycle control. Whereas neural stem cells are regulated by
the cyclin-dependent kinase inhibitor, p21Cip1(Kippin et al.,
2005), another family member, p27Kip1, regulates restricted
progenitor proliferation (Cheng et al., 2000; Doetsch et al.,
2002). Other cell-cycle regulators and tumor suppressors
consolidate the transition of stem cells into transit-amplifying
progenitors by negatively regulating self-renewal. Deletion of
p16Ink4a, p19Arf, and p53 dramatically expands HSC frequency
by restoring long-term self-renewal potential to progenitors
that normally only transiently self-renew (Akala et al., 2008).
These tumor suppressors also limit the reprogramming of
fibroblasts into iPS cells (Banito et al., 2009; Hanna et al.,
2009; Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009;
Mario ´n et al., 2009; Utikal et al., 2009). Tumor suppressors
that negatively regulate cell-cycle progression thus inhibit the
acquisition of stem cell identity, perhaps by negatively regulating
Access to Niche Signals Can Distinguish
Stem Cells from Restricted Progenitors
Many stem cells reside in specialized microenvironments, called
niches, which promote stem cell maintenance and regulate stem
cell function (Morrison and Spradling, 2008). One of the best-
characterized niches is the Drosophila testis, in which spermato-
cells through DE-cadherin and b-catenin/armadillo-mediated
adherens junctions (Figure 1B) (Fuller and Spradling, 2007). In
addition to anchoring stem cells within the niche, hub cells
secrete short-range signals (Unpaired, a ligand that activates
JAK/Stat signaling, and Decapentaplegic, a BMP homolog)
that promote stem cell maintenance. Spermatogonial stem cells
divide asymmetrically, oriented by the axis created by mother
and daughter centrosomes, such that one daughter cell remains
undifferentiated within the niche and the other daughter cell is
displaced from the niche and fated to differentiate (Figure 1B)
(Yamashita et al., 2007). Short-range niche signals can therefore
determine the size of the stem cell pool (based on the space
available in the niche), aswell aswhich cellsare fatedto differen-
tiate (based on whether they are displaced from the niche)
The C. elegans germline niche is conceptually similar in that
spatially restricted Notch ligands expressed by the distal tip
cell at the end of the gonad are required for the maintenance
of undifferentiated stem cells. Cells displaced from the distal
the Drosophila germline, there is no evidence that C. elegans
germline stem cells undergo asymmetric divisions. Stem cells
thus undergo both asymmetric and symmetric divisions within
their niches, depending on tissue and developmental context
(reviewed in Morrison and Kimble, 2006).
Figure 1. Some Mechanisms Promote Stem Cell
Self-Renewal in Multiple Tissues but Do Not
Promote the Proliferation of All Progenitors
(A) A schematic depiction of stem cells from two different
tissues givingrise totheirrespective restricted progenitors
and differentiated cells. The yellow nucleus denotes that
intrinsically promote stem cell maintenance are conserved
across tissues; however, these mechanisms are not
necessarily required by restricted progenitors or differen-
Bmi-1, Sox17, Prdm16, and Hmga2 (see main text for
details and references).
(B) Stem cells also depend upon extrinsic short-range
signals from the niche (yellow cells) for their maintenance.
Niches in different tissues and different species often
employ similar strategies, and even similar secreted
factors, to promote stem cell maintenance. Stem cells
often depend upon Wnt, Notch, and/or BMP ligands
secreted by the niche for their maintenance. Exposure to
this short-range signal from the niche distinguishes stem
cells (yellow nucleus) from progenitors fated to differen-
tiate, and the size of the niche determines the number of
stem cells in the tissue. Cells displaced from the niche by
cell division or competition are fated to differentiate (Fuller
and Spradling, 2007; Morrison and Spradling, 2008).
(C) Stem cells are also extrinsically regulated by long-
range signals that reflect nutritional status, oxygen level,
hormonal status, or other physiological changes.
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Mammalian tissues also have specialized niches that secrete
short-range factors that promote stem cell maintenance (Morri-
son and Spradling, 2008). As in the niches characterized in
Drosophila and C. elegans, Notch ligands, BMPs, and Wnt
proteins have been implicated in the regulation of stemcellmain-
tenance in multiple mammalian tissues, including in the CNS
(Doetsch, 2003) and in hair follicles (Blanpain and Fuchs, 2006).
These factors are presumed to be locally secreted by supporting
Stem cells are also extrinsically regulated by long-range
signals, including an evolutionarily conserved role for insulin
pathway regulation (Figure 1C). Circulating insulin-like peptide
isrequiredforthemaintenance ofDrosophila germline stemcells
and intestinal stem cells, and quantitative changes in nutritional
status lead to changes in stem cell function as a result of
changing insulin-like peptide levels (LaFever and Drummond-
Barbosa, 2005; McLeod et al., 2010). Mammalian stem cells
are also positively regulated by insulin signaling as fetalforebrain
stem cells adjacent to the lateral ventricle are regulated by IGF2
in cerebral spinal fluid (Lehtinen et al., 2011). Nonetheless, addi-
tional work will be required to determine whether mammalian
stem cells are regulated by systemic nutritional status.
Aging Has Similar Effects on Stem Cells
in Multiple Tissues
Aging is associated with reduced regenerative capacity and
stem cell function in multiple tissues, including the CNS
(Figure 2C) (Maslov et al., 2004). Stem cell function decreases
with age in many tissues in an evolutionarily conserved manner.
Fly spermatogonial stem cell function declines during aging as
a consequence of both cell-intrinsic (Cheng et al., 2008) and
niche changes (Boyle et al., 2007). In aging mammalian tissues,
stem cells exhibit reduced self-renewal potential and accumula-
tion of damage to DNA, mitochondria, and other macromole-
cules (Rossi et al., 2008; Sharpless and DePinho, 2007).
The declines in stem cell function during aging are also asso-
ciated with increasing tumor suppressor expression (Figure 2B).
The p16Ink4acyclin-dependent kinase inhibitor, a negative regu-
lator of cell-cycle progression that sometimes causes cellular
senescence, is generally not detectable in young adult tissues,
but expression increases during aging (Krishnamurthy et al.,
2004). This increase in p16Ink4aexpression contributes to the
age-related decline in stem cell function in the hematopoietic
and nervous systems, as well as the decline in b cell proliferation
in the pancreas. Deficiency for p16Ink4apartially rescues the age-
related declines in stem cell frequency, mitotic activity, and
Figure 2. Stem Cell Self-Renewal Mechanisms
Change with Age
(A) A pathway of tumor suppressors (red) and proto-
oncogenes (green) that control stem cell self-renewal and
that change in expression with age (Nishino et al., 2008).
decreases with age in stem cells.
(B) The balance between proto-oncogenic signals and
gate-keeping tumor suppressor signals changes with age
within stem cells (Levi and Morrison, 2008). Proto-onco-
genic signals dominate during fetal development when
stem cells divide rapidly, and some gate-keeping tumor
suppressor mechanisms that are critical during adulthood
are not competent to negatively regulate division in fetal
stem cells. Proto-oncogenes and gate-keeping tumor
suppressors come into balance in young adult stem cells,
which are often quiescent but remain able to enter cycle
to regenerate tissues after injury. Gate-keeping tumor
suppressors, such as p16Ink4a, predominate in aging stem
cells, which exhibit less regenerative potential.
(C) The changing balance between proto-oncogenes and
tumor suppressors allows stem cells to change their
properties throughout life in a way that mirrors changing
tissue demands. Tissue growth and regenerative capacity
decline over time, whereas cancer incidence increases.
The increasing tumor suppressor expression during aging
may attenuate the increasing cancer incidence in aging
tissues at the cost of reducing tissue-regenerative
capacity.Increasing expressionofthe gate-keeping tumor
suppressors p16Ink4aand p19Arfincreasesmouse life span
through mechanisms beyond reducing cancer incidence
(Matheu et al.,2009).Thissuggests that it isadvantageous
to negatively regulate the proliferation of some cells in
aging tissues, despite the consequent reduction in stem
cell function and tissue regeneration.
(D) Unrepaired DNA damage (red crosses) accumulates
with age to a greater extent in stem cells as compared to
restricted progenitors (Rossi et al., 2007). Cell-extrinsic
factors also modulate stem cell aging. Muscle satellite cell
function declines with age as these cells are exposed to
a decreased level of Notch ligands and increased levels of
Wnt and TGFß (Brack et al., 2007; Carlson et al., 2008;
Conboy et al., 2003; Conboy et al., 2005; Liu et al., 2007).
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neurogenesis in the forebrain (Molofsky et al., 2006), as well as
increasing HSC frequency (Janzen et al., 2006) and increasing
the regenerative capacity of pancreatic b cells (Krishnamurthy
et al., 2006). These results suggest that aging stem cells actively
sion of tumor suppressors (Figure 2). This increase in tumor
suppressor expression presumably reduces cancer incidence
in aging tissues, because p16Ink4a-deficient mice exhibit
a much higher cancer incidence during aging (Sharpless et al.,
A pathway controlled by let-7 microRNAs changes with age to
allow increased p16Ink4aexpression in stem cells (Figure 2A). In
mouse neural stem cells, let-7b expression increases with age,
reducing the expression of the Hmga2 transcriptional regulator
and increasing the expression of the JunB, p16Ink4a, and p19Arf
tumor suppressors (Nishino et al., 2008). Hmga2 promotes
stem cell self-renewal in fetal and young adult tissues by nega-
tively regulating the expression of p16Ink4aand p19Arf, allowing
these genes to be expressed in aging tissues as Hmga2 expres-
sion is extinguished by increasing let-7b expression. This
pathway is likely to regulate age-related changes in stem cell
function in multiple tissues without generically regulating the
proliferation of all cells, because Hmga2 is not required to
promote the proliferation of restricted neuronal or glial progeni-
tors (Nishino et al., 2008).
These results demonstrate that stem cell self-renewal is regu-
lated by networks that balance proto-oncogenes, like Bmi-1 and
Hmga2, with gate-keeping tumor suppressors, like p16Ink4aand
p19Arf(Pardal et al., 2005). The way stem cells balance these
competing signals changes with age (Figure 2B) (Levi and
Morrison, 2008). Proto-oncogenic signals dominate during fetal
development when stem cells divide rapidly to form tissues
and when there is little risk of cancer. The proto-oncogenic
signals come into balance with gate-keeping tumor suppressors
during young adulthood, when most stem cells are quiescent
most of the time and when tumor suppression is required to
avoid cancer. During aging, gate-keeping tumor suppressor
expression increases. This reduces stem cell function and tissue
regenerative capacity, as well as presumably reducing cancer
incidence. By undergoing temporal changes in the balance
between proto-oncogenic and tumor suppressor signals, stem
cells favor growth over tumor suppression during fetal develop-
ment and tumor suppression over tissue regeneration in aging
tissues (Figure 2C).
This might also explain why mutation spectrum differs in child-
hood versus adult cancers (Downing and Shannon, 2002). If self-
renewal pathways change with age, then different mutations
may be competent to promote neoplastic proliferation in cells
from different age patients.
Failure to repair DNA damage leads to phenotypes that
resemble premature aging, including a premature decline in
stem cell function (Blanpain et al., 2011; Rossi et al., 2008). Defi-
ciencies in DNA repair proteins significantly reduce stem cell
function, particularly under stressful conditions (Ito et al., 2004;
Nijnik et al., 2007; Rossi et al., 2007). HSCs and primitive hema-
topoietic progenitors accumulate DNA lesions during aging,
marked by gH2AX foci (Figure 2D) (Rossi et al., 2007). DNA
damage may accumulate in HSCs because quiescent HSCs
have enhanced survival mechanisms compared to differentiated
progenitors and rely on error-prone nonhomologous end joining
to repair DNA double-strand breaks (Mohrin et al., 2010). The
reliance upon nonhomologous end joining to repair DNA
double-strand breaks is also observed in epidermal stem cells
(Sotiropoulou et al., 2010), but not in all stem cells (Blanpain
et al., 2011). Stem cells thus share mechanisms to suppress
the accumulation of DNA damage. Although experimental
elimination of DNA repair mechanisms leads to a premature
depletion of stem cells, an open question is the extent to which
DNA damage in stem cells affects the properties of these cells
during physiological aging.
contribute to the aging of stem cells (Figure 2D). Aging reduces
the regenerative capacity of muscle satellite cells through
increases in the levels of Wnt and TGF-b and a decrease in the
expression of Notch ligands (Brack et al., 2007; Carlson et al.,
2008; Conboy et al., 2003; Conboy et al., 2005; Liu et al.,
2007). Declines in mitochondrial function are also observed
during aging (Balaban et al., 2005; Chan, 2006) and can be
precipitated by premature declines in telomere length as
a consequence of telomerase deficiency (Sahin et al., 2011).
Given that defects in mitochondrial function can yield pheno-
types that resemble premature aging (Balaban et al., 2005;
Chan, 2006), these results suggest that defects in energy me-
tabolism are one mediator of the effects of telomere attrition
and stem cell maintenance. Stem cells express telomerase to
attenuate the decline in telomere length with age or upon tissue
regeneration (Morrison et al., 1996; Vaziri et al., 1994). Telome-
rase deficiency leads to reduced stem cell self-renewal, stem
cell depletion, and defects in the regeneration of proliferative
tissues (Allsopp et al., 2003; Ferro ´n et al., 2004; Jaskelioff
et al., 2011; Lee et al., 1998). In telomerase-deficient mice, these
defects are only observed beginning in the third generation after
loss of telomeres or upon serial transplantation of HSCs;
however, inbred mice have much longer telomeres and shorter
life spans than humans. It therefore remains uncertain whether
telomere length is limiting for stem cell function or tissue
regeneration in the context of normal human aging. Surprisingly,
reactivation of telomerase can elongate telomeres, rescuing
epithelial stem cell function (Flores et al., 2005), as well as neural
stem cell function, neurogenesis, and olfactory function in
telomerase-deficient mice (Jaskelioff etal., 2011). The regulation
of telomerase activity is thus critical for the maintenance of stem
cell function and tissue regenerative capacity.
Energy Metabolism in Stem Cells
Stemcellsmustdynamically reprogramtheir cellularmetabolism
in response to changes in cell-cycle status, which can occur
during normal development or after injury. The ways in which
they change their metabolism are not yet understood but
presumably involve activation of nutrient uptake and consump-
tion, and changes in the biosynthetic pathways that support
survival and proliferation (DeBerardinis et al., 2008; Vander
Heiden et al., 2009). Disruption of the mechanisms that regulate
these metabolic pathways can lead to profound defects in stem
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
cells without necessarily having the same effects on restricted
et al., 2010; Nakada et al., 2010). This suggests that some meta-
bolic pathways are regulated differently in stem cells as
compared to their progeny.
Stem cells and their differentiated progeny have distinct meta-
bolic profiles. Cultured ES cells rely on glycolysis for ATP
production but upregulate mitochondrial oxidative metabolism
as they differentiate (Facucho-Oliveira and St John, 2009).
Pluripotent cells in the inner cell mass also rely on glycolysis
and upregulate oxidative metabolism during development
otent cells therefore rely upon glycolysis for ATP production
in vitro and in vivo, perhaps because glycolysis also yields
substrates for anabolic biosynthetic pathways that proliferating
cells depend upon (Vander Heiden et al., 2009). Adult HSCs
have reduced concentrations of ATP and fewer mitochondria
than differentiated cells and have been suggested to rely on
glycolysis to generate ATP, even though these cells are mainly
quiescent (Inoue et al., 2010; Kim et al., 1998; Simsek et al.,
2010). This raises the possibility that many undifferentiated
stem cells preferentially rely upon glycolysis, irrespective of
whether they are highly proliferative or quiescent.
Stem cells must coordinate energy metabolism with cell
division. The PI-3kinase pathway is activated in response to
various growth factors and promotes cell growth and prolifera-
tion, partly by activating Akt and mTORC1 (Figure 3) (Engelman
et al., 2006). The Pten tumor suppressor negatively regulates
PI-3kinase pathway signaling, and Pten deficiency increases
cell growth and proliferation. Deletion of Pten increases the
self-renewal of ES cells, as well as in vivo neurogenesis and
in vitro self-renewal by CNS stem cells (Gregorian et al., 2009;
leads to their depletion by activating a tumor suppressor
response marked by increased p16Ink4aand p53 expression
(Lee et al., 2010; Yilmaz et al., 2006; Zhang et al., 2006). Deletion
of TSC also leads to HSC depletion, partly by increasing
mitochondrial mass and oxidative stress (Chen et al., 2008;
Gan et al., 2008).
The Lkb1-AMPK kinases are key regulators of cellular metab-
olism that coordinate cellular proliferation with energy metabo-
lism by suppressing proliferation when the ATP to AMP ratio is
low. EnergystresspromptsAMPK signaling to activate catabolic
pathways such as mitochondrial fatty acid oxidation while inhib-
iting anabolic pathways such as mTORC1-mediated protein
synthesis (Figure 3) (Shackelford and Shaw, 2009). Lkb1 is
a tumor suppressor that is mutated in Peutz-Jeghers syndrome
patients (Hemminki et al., 1998; Jenne et al., 1998). Lkb1
deficiency increases the proliferation of many tissues (Contreras
et al., 2008; Gurumurthy et al., 2008; Hezel et al., 2008; Pearson
et al., 2008) and immortalizes mouse embryonic fibroblasts
(Bardeesy et al., 2002). These data suggest that the primary
function of Lkb1 in many adult tissues is to negatively regulate
cell division, preventing tissue overgrowth. However, conditional
deletion of Lkb1 from hematopoietic cells leads to a cell-auton-
omous defect in HSCs that rapidly increases proliferation and
cell death (Gan et al., 2010; Gurumurthy et al., 2010; Nakada
et al., 2010). HSCs depend more acutely on Lkb1 for cell-cycle
regulation and survival as compared to other hematopoietic
cells. Lkb1 also has different effects on signaling pathways and
progenitors (Nakada et al., 2010). This demonstrates that even
key metabolic regulators have different functions in different
kinds of dividing somatic cells.
The Lkb1 pathway regulates chromosome stability in HSCs in
addition to energy metabolism. Lkb1-deficient HSCs exhibit
supernumerary centrosomes and become aneuploid, whereas
myeloid-restricted progenitors appear to divide normally in the
absence of Lkb1 (Nakada et al., 2010). AMPK-deficient HSCs
do not become aneuploid, indicating that Lkb1 regulates mitosis
in HSCs through AMPK-independent mechanisms. Lkb1 and
AMPK homologs in Drosophila also regulate chromosome
stability in neuroblasts, suggesting that Lkb1 is an evolu-
tionary-conserved regulator of mitosis in some cell types
(Bonaccorsi et al., 2007; Lee et al., 2007). Therefore, regulation
of mitotic processes including chromosome segregation differs
between stem cells and some other progenitors.
Stem Cells Are Sensitive to Oxidative Stress
Stem cells are particularly sensitive to the toxic effects of oxida-
tive damage and are equipped with protective mechanisms that
appear to be less active in some other progenitors. FoxO
Figure 3. Signaling Pathways that Regulate Energy and Oxygen
Metabolism in Stem Cells
Various growth factors activate PI-3kinase through their receptors, leading to
activation of Akt (Engelman et al., 2006). Akt activation leads to mTORC1
activation, which promotes protein translation and lipid synthesis. The Lkb1-
AMPK pathway becomes activated upon energy stress and inhibits the
mTORC1 pathway by activating TSC (Shackelford and Shaw, 2009). Akt also
negatively regulates FoxO transcription factor function. FoxO transcription
factors promote the expression of enzymes that detoxify ROS (Salih and
Brunet, 2008). Other transcriptional/epigenetic regulators, such as Bmi1 and
Prdm16, also regulate oxidative stress and mitochondrial function. HIF tran-
scription factors are stabilized in hypoxia by the inhibition of von Hippel Lindau
(VHL)-mediated degradation. HIF promotes glucose uptake and glycolysis to
adapt to hypoxia. Red ovals indicate tumor suppressors, green ovals indicate
proto-oncogenes, and yellow ovals indicate proteins whose role in tumori-
genesis is not clear.
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
transcription factors regulate stem cell maintenance by regu-
lating the expression of genes involved in cell cycle, apoptosis,
oxidative stress, and energy metabolism (Figure 3) (Salih and
Brunet, 2008). Deletion of FoxO1, 3, and 4 in CNS stem cells or
in mouse HSCs leads to increased levels of reactive oxygen
species (ROS) and to stem cell depletion (Paik et al., 2009;
Tothova et al., 2007). Treating FoxO-deficient mice with the anti-
oxidant N-acetyl-L-cysteine partially rescues these stem cell
defects. FoxO3 appears to be the most important FoxO for
stem cell function, because deletion of FoxO3 alone also
depletes CNS stem cells and HSCs (Miyamoto et al., 2007;
Renault et al., 2009; Yalcin et al., 2008). In contrast to HSCs,
FoxO-deficient restricted myeloid progenitors do not exhibit
increased ROS levels (Tothova et al., 2007). This suggests that
stem cells depend more upon FoxO transcription factors than
certain downstream progenitors.
Prdm16 is another transcription factor that promotes stem cell
maintenance in multiple tissues, at least partly by regulating
oxidative stress (Figure 3). Prdm16 is a zinc finger protein that
was originally identified as part of a chromosomal translocation
in some human acute myeloid leukemias (Morishita, 2007).
Consistent with this, overexpression of the Prdm16 proto-onco-
gene can immortalize myeloid cells (Nishikata et al., 2003);
however, the physiological role of Prdm16 is to regulate stem
cell function in multiple tissues. Prdm16 is necessary for the
development of brown fat cells (Seale et al., 2008), as well as
for the maintenance of stem cell activity in the nervous and
hematopoietic systems (Chuikov et al., 2010). The depletion of
neural stem cells is at least partially due to increased oxidative
stress, because the depletion can be partially rescued by treat-
ment with N-acetyl-L-cysteine. Prdm16 appears to regulate
mitochondrial function and to prevent the accumulation of
ROS, though the mechanisms by which this occurs remain
The polycomb protein Bmi-1 promotes stem cell maintenance
by negatively regulating p16Ink4aand p19Arfexpression (Brugge-
et al., 2006) and likely by regulating mitochondrial function and
oxidative stress as well (Figure 3) (Liu et al., 2009). Cells from
Bmi1-deficient mice have reduced mitochondrial oxygen
reduced ATP levels, and elevated ROS levels that appear to
cause DNA damage (Liu et al., 2009). Treating Bmi1-deficient
mice with N-acetyl-L-cysteine partially rescues the depletion of
thymocytes, though it has not yet been tested whether this
also rescues stem cell function. The observation that Bmi-1
regulates tumor suppressor expression and mitochondrial func-
tion suggests that key self-renewal mechanisms integrate
to PI-3kinase pathway regulation by Pten, AMPK, and Lkb1.
Although elevated ROS levels are toxic to stem cells, physio-
logical levels of ROS are required for certain stem cell functions.
Consistent with the role of Akt in negatively regulating FoxO
function (Salih and Brunet, 2008), deletion of Akt1 and Akt2
entiation of HSCs (Juntilla et al., 2010). Neural stem/progenitor
cell proliferation and differentiation are also regulated by ROS
(Le Belle et al., 2011; Prozorovski et al., 2008; Smith et al., 2000).
Stem Cells, Oxygen, and Hypoxia
Changes in stem cell function are involved in the adaptation to
declining oxygen availability, such as those that occur with
increasing altitude or cardiopulmonary disease. Neuron-like
glomus cells in the carotid body mediate these responses by
sensing oxygen levels in the blood and inducing hyperventilation
during hypoxemia. Exposure of mice to hypoxia induces the
proliferation of glia-like stem cells that remodel the carotid
body in response to hypoxia to increase the number of glomus
cells (Pardal et al., 2007). Hypoxia also increases erythropoiesis
by inducing erythropoietin expression in the kidney and liver
(Semenza, 2009). Hypoxia increases the total number and prolif-
eration of HSCs and multipotent progenitors (Li et al., 2011). It is
possible that this involves indirect effects of hypoxia on cell
death or cell turnover. Alternatively, because most HSCs localize
close to blood vessels (Kiel et al., 2005; Me ´ndez-Ferrer et al.,
2010), it is possible that their niche senses changes in oxygen
levels. Because other stem cells, including some neural stem
cells (Mirzadeh et al., 2008; Shen et al., 2008), also reside in peri-
vascular microenvironments, it is conceivable that stem cells in
multiple tissues are directly influenced by oxygen levels
(Figure 4). Regardless of the mechanisms, multiple tissues are
remodeled in response to hypoxia, partly due to changes in
stem/progenitor cell function.
It has been hypothesized that most stem cells reside in
hypoxic niches that enable them to suppress oxidative damage
by relying upon glycolysis rather than mitochondrial oxidative
phosphorylation (Mohyeldin et al., 2010; Parmar et al., 2007;
Simsek et al., 2010); however, this has not yet been tested in
most tissues or in most developmental contexts. Hypoxic
microenvironments may not protect stem cells from oxidative
stress because hypoxia, paradoxically, can lead to the genera-
tion of elevated ROS levels (Brunelle et al., 2005; Guzy and
Schumacker, 2006). Nonetheless, evidence suggests that
many bone marrow HSCs and at least some neural stem cells
in adult mice reside in hypoxic environments. This may appear
superficially inconsistent with the idea that HSCs often reside
perivascularly; however, HSCs reside adjacent to sinusoidal
blood vessels in hematopoietic tissues (Kiel et al., 2005).
Sinusoids are a specialized form of vasculature found only in
hematopoietic tissues. Sinusoids carry slow veinous circulation
that is not designed to transport oxygen around the body as
much as to provide specialized vasculature through which
hematopoietic cells can intravasate into circulation. Thus, the
perisinusoidal environment in the bone marrow may be relatively
Stem cell maintenance also depends upon mechanisms that
factor 1a (HIF1a) is a transcription factor that is stabilized in
response to hypoxic stress, activating the expression of genes
that promote nonoxidative carbon metabolism and ATP
synthesis, such as those involved in glucose import and glycol-
ysis (Figure 3) (Majmundar et al., 2010). Deletion of HIF1a from
neural stem cells depletes neurogenic progenitors in the subgra-
nular zone of the dentate gyrus (Mazumdar et al., 2010). HIF1a
deletion also leads to a progressive decline in HSC function
during bone marrow transplantation or aging (Takubo et al.,
2010). Deletion of von Hippel Lindau, which encodes a ubiquitin
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
ligase involved in the degradation of HIF1a, also leads to HSC
defects, even though this increases HIF1a levels (Takubo et al.,
2010). This suggests that HIF1a levels must be tightly regulated.
Stem cells likely depend on a variety of mechanisms to maintain
Changes in Nutrition Affect Stem Cell
Function in Many Tissues
Caloric restriction increases longevity and reduces age-related
disease in an evolutionarily conserved manner (Bishop and
Guarente, 2007), partly by influencing the function of stem and
progenitor cells. Caloric restriction in rodents enhances neuro-
genesis in the dentate gyrus by promoting the survival of
newborn neurons and astrocytes (Bondolfi et al., 2004; Lee
et al., 2002) and potentially by increasing progenitor proliferation
(Kumar et al., 2009). In the hematopoietic system, short-lived
mouse strains exhibit a decline in HSC frequency and function
during aging, whereas long-lived mouse strains do not
(de Haan et al., 1997). Caloric restriction attenuates the age-
related decline in HSC frequency in at least one short-lived
mouse strain (Ertl et al., 2008). Feeding adult Drosophila a low-
nutrient diet alleviates the age-related reduction in the number
and proliferation of male germline stem cells (Mair et al., 2010).
Caloric restriction can therefore attenuate the reduction in
stem cell function during aging in multiple tissues and species.
Nutritional changes can alter the expression of systemic
factors that regulate stem cells (Figure 4). Protein starvation in
Drosophila leads to a reversible loss of male germline stem cells
peptides, possibly by insulin-producing cells in the brain
(McLeod et al., 2010). Expression of constitutively active insulin
linestemcells,suggesting thatinsulindirectlyregulates germline
stem cell maintenance. This allows stem cell function in multiple
tissues to be modulated by changes in nutritional status.
Changes in the nutritional status of the organism can also indi-
rectly affect stem cell function by modulating the environment
(Figure 4). Reduced insulin signaling after protein starvation
reduces the proliferation of Drosophila female germline stem
cells by acting directly on these cells and by reducing the
capacity of the niche to maintain these cells (Hsu and Drum-
mond-Barbosa, 2009; LaFever and Drummond-Barbosa, 2005).
Whereas decreased nutrition can reduce stem cell function,
increased nutrition can increase stem cell function. Upon
feeding, fat cells in Drosophila activate TOR signaling and
secrete a fat-body-derived signal that regulates insulin-like
peptide secretion by a subpopulation of nutritionally regulated
glial cells. This insulin-like peptide activates neuroblast prolifer-
ation through PI-3kinase/TOR signaling (Chell and Brand,
2010; Sousa-Nunes et al., 2011). Additional work will be required
to assess whether mammalian stem cells are also acutely regu-
lated by changes in nutritional status.
The Stem Cell Response to Injury and Disease
Regeneration in many adult tissues involves the activation of
stem cells to enter cycle and to increase the generation of differ-
entiated cells. Loss of hematopoietic cells by cytotoxicity
(Harrison and Lerner, 1991) or bleeding (Cheshier et al., 2007)
leads to HSC expansion, mobilization from the bone marrow,
andextramedullaryhematopoiesis in the liverand spleen. Stroke
and excitotoxic injuries induce cell death in the brain, but stem
cells appear more resistant to these stresses and initiate
a wound-healing response that increases neural progenitor
proliferation and neurogenesis (Parent, 2003; Romanko et al.,
2004). Neural stem cells in the forebrain subventricular zone
migrate to the siteof injury and generate newneurons (Arvidsson
et al., 2002; Parent et al., 2002; Yamashita et al., 2006). The
physiological significance of this CNS injury response is uncer-
tain, because most of these new neurons are short lived, fail to
incorporate into neural circuits, and appear to contribute little
to functional recovery (Zhao et al., 2008). Nonetheless, these
Figure 4. Integrating Stem Cell Function with Systemic Physiology
Physiological changes experienced by animals cause changes in stem cell
function that lead to adaptive changes in tissue growth and remodeling. Stem
cell function is modulated by long-range extrinsic signals that reflect changes
in nutrition (A), circadian regulation (B), hormones (C and D), and oxygen
tension (E). These signals sometimes act directly on stem cells and sometimes
act on niche cells to indirectly modulate stem cell function (see main text for
details and references). The CNS is integral to the coordination of many
physiological changes through neural activity (B) and the secretion of
(A) Stem cell function is modulated by insulin and other signals that reflect
(B) Stem cells are regulated by circadian rhythms generated centrally in the
suprachiasmatic nucleus (SCN) of the brain and conveyed through the
sympathetic nervous system (SNS).
(C and D) Sexual maturation, mating, and pregnancy can influence stem cell
function by changing the expression of hormones from the gonads (C) and the
pituitary gland (D).
(E) Physiological changes also modulate stem cell function by altering oxygen
levels and systemic levels of cytokines and growth factors in the blood.
Dashed arrows indicate factors secreted from the indicated organ that act on
stem cells and their niches in multiple target tissues (green and orange).
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
responses illustrate the existence of mechanisms across tissues
that activate stem cells in response to injury.
Inflammation modulates stem cell function in response to
infection or injury. Bacterial and viral infections induce inter-
ferons, driving adult HSCs into cycle and expanding HSC
numbers (Baldridge et al., 2010; Essers et al., 2009; Sato et al.,
2009). This response must be highly regulated, because chronic
activation in many contexts leads to HSC depletion (Baldridge
et al., 2010; Essers et al., 2009; Sato et al., 2009). Inflammation
also inhibits neurogenesis and neural stem cell function in vivo
(Ekdahl et al., 2003; Li et al., 2010; Monje et al., 2003). Pharma-
cological anti-inflammatory agents restore dentate gyrus neuro-
genesis after inflammation induced by irradiation (Monje et al.,
2003). Microglial cells mediate the effect of inflammation on
neurogenesis (Butovsky et al., 2006). Inflammatory signals can
likely have both local and systemic effects on stem cell function,
and much more study will be required to fully understand the
influence of inflammation on stem cell function.
Circadian Regulation of Stem Cell Function
Circadian rhythms regulate many aspects of metabolism and
physiology, including stem cell function (Figure 4). Circadian
rhythms are evolutionarily conserved cyclical variations in gene
expression and function that are approximately a day in length
and are observed in cells from bacteria to mammals (Takahashi
et al., 2008). The vertebrate CNS controls circadian rhythms
throughout the body with oscillations of a master clock located
in the suprachiasmatic nucleus of the hypothalamus (Figure 4).
This master clock is entrained by light received by the retina,
generating a transcriptional autoregulatory loop composed of
the transcriptional activators Clock and Bmal1 and their target
genes and feedback inhibitors Period1-3 (Per) and Crypto-
chrome1-2 (Cry) (Bass and Takahashi, 2010). Circadian rhythms
regulate the expression of genes involved in protein turnover,
mitochondrial respiration, and lipid and glucose metabolism
(Panda et al., 2002; Rutter et al., 2002) and are proposed to allow
temporal orchestration of metabolic processes to maximize the
utilization of nutrients (Tu and McKnight, 2006).
The circadian regulation of stem cells has been most exten-
sively studied in the hematopoietic system (Figure 4). Circadian
oscillations affect DNA synthesis and the frequency of colony-
forming hematopoietic progenitors in mice and humans
(Me ´ndez-Ferrer et al., 2009), the ability of sublethally irradiated
mice to engraft with transplanted bone marrow cells (D’Hondt
et al., 2004), and the susceptibility of bone marrow to chemo-
therapy (Le ´vi et al., 1988). All of these phenomena may reflect
the influence of circadian regulation on the timing of cell division
byhematopoietic cells, as this has been observed in a number of
tissues (Me ´ndez-Ferrer et al., 2009; Takahashi et al., 2008).
Circadian rhythms also regulate neurogenesis in the hippo-
campus of multiple species, with increased proliferation at
a specific circadian phase depending on the species (Goergen
et al., 2002; Guzman-Marin et al., 2007).
HSCs and other progenitors are regularly mobilized from the
bone marrow into circulation and then back into hematopoietic
oscillating expression of the chemokine Cxcl12, and its receptor
the inactive (light) phase of the cycle, allowing mobilization of
hematopoietic progenitors into the blood (Katayama et al., 2006;
Lucas et al., 2008; Me ´ndez-Ferrer et al., 2008). This effect is also
observedinhumans, althoughthe human diurnal cycle isinverted
iological significance of this mobilization is not clear.
Exercise, Mating, and Pregnancy
Exercise, sex hormones, mating, and pregnancy all have effects
neural stem cells and enhances cognitive parameters in mice
and humans, including learning and memory (Hillman et al.,
2008). Exercise affects many aspects of energy metabolism,
leading to the consumption of stored nutrients, as well as
hypoxia when exercise becomes anaerobic. In adult mice of all
ages, voluntary running stimulates cell proliferation and neuro-
genesis in the hippocampus (van Praag et al., 1999; van Praag
et al., 2005). Neurogenesis and neural stem cell frequency in
the forebrain subventricular zone are increased by exercise as
well (Blackmore et al., 2009).
The neurogenic response to exercise is likely to be mediated
by multiple systemic factors. Growth hormone and insulin-like
growth factor 1 (IGF1) expression are activated in rodents
upon exercise (Carro et al., 2000; Eliakim et al., 1997). Growth
hormone receptor-deficient mice did not show an increase of
neurogenesis after voluntary exercise (Blackmore et al., 2009).
Much of the activity of growth hormone is exerted through the
production of IGF1, which is largely produced in the liver
(Jones and Clemmons, 1995). Exercise stimulates the uptake
of blood-borne IGF1 by specific groups of neurons involved in
adaptive responses to exercise, and subcutaneous administra-
tion of IGF1 is sufficient to induce neurogenesis in the dentate
gyrus (Carro et al., 2000). Antibody inhibition of IGF1 blocks
theneurogenic andproliferativeeffects ofexerciseinthedentate
gyrus (Trejo et al., 2001). These data suggest a systemic
response to exercise that influences the behavior of neural
stem cells and potentially stem cells in other tissues.
Courtship and pregnancy stimulate sex-specific changes in
from those induced byexercise. The estrus cycle and pregnancy
in female mice are characterized by distinct patterns of gonadal
hormones (Figure 4). During pregnancy, neurogenesis increases
to be important for the recognition and rearing of offspring
(Shingo et al., 2003). Prolactin is sufficient to induce neurogene-
sis andmay actdirectly on neural stemcells (Shingo et al.,2003).
In addition to pregnancy, exposure of female mice to male
pheromones also induces neurogenesis (Mak et al., 2007).
Pheromones from dominant males stimulate neurogenesis in
the forebrain subventricular zone and in the dentate gyrus by
inducing prolactin and luteinizing hormone, respectively. Neuro-
genesis stimulated by male pheromones affects mating prefer-
ence and, consequently, the success of offspring (Mak et al.,
fore induce adaptive behavioral changes.
There are additional physiological demands on pregnant
and mating animals beyond neural adaptation. Mammalian
Neuron 70, May 26, 2011 ª2011 Elsevier Inc.
mammary tissue is acutely sensitive to hormonal regulation that
leads to profound changes in morphology and function.
Estrogen and progesterone promote the expansion of mammary
stem cells and mammary gland morphogenesis (Figure 4) (Asse-
lin-Labat et al., 2010; Joshi et al., 2010). These steroid hormones
induce expression of Wnt and RANK ligands by luminal cells,
which then act on mammary stem cells to induce proliferation,
resulting in more than 10-fold expansion of mammary stem cell
frequency during pregnancy and the estrus cycle (Asselin-Labat
et al., 2010; Joshi et al., 2010). The regular expansion and
contraction of the mammary stem cell pool during each
menstrual cycle provides a potential explanation for why breast
cancer risk increases with the number of menstrual cycles in
humans (Clemons and Goss, 2001). The hematopoietic system
also undergoes considerable alterations during pregnancy,
increasing erythropoiesis and extramedullary hematopoiesis
(Fowler and Nash, 1968). Stem cells in multiple tissues are there-
fore likely to respond to global physiological cues that remodel
tissues in response to pregnancy and sex hormones.
Stem cells are regulated by diverse physiological cues that inte-
grate stem cell function and tissue remodeling with physiological
demands. Stem cell function is modulated by circadian rhythms,
changes in metabolism, diet, exercise, mating, aging, infection,
and disease. It is likely that these physiological changes have
systemic effects on stem cells in multiple tissues.
Diverse transcriptional, metabolic, cell cycle, and signaling
mechanisms regulate stem cell function without generically
regulating the function of all dividing cells. Many factors critical
for stem cell maintenance regulate energy metabolism and
oxidative stress. The concerted regulation of energy metabolism
and stem cell function may allow stem cell function to be closely
matched to nutritional status. Understanding the key differences
between stem cells and other progenitors should provide impor-
tant insights into how tissue homeostasis is maintained
throughout life and how regeneration might be enhanced by
therapies that modulate stem cell metabolism.
Understanding these mechanisms could also improve the
treatment of cancer. Proto-oncogenes and tumor suppressors
likely evolved to regulate stem cell function and tissue homeo-
stasis, but cancer cells hijack these mechanisms to enable
neoplastic proliferation. Proto-oncogenic pathways such as the
PI-3kinase pathway are frequently overactivated in cancer, acti-
vating autonomous nutrient uptake, factor-independent growth,
and survival, increasing glycolysis and anabolic pathways (De-
Berardinis et al., 2008). Collectively, this promotes aerobic
glycolysis, also called the Warburg effect, in which cancer cells
consume glucose by glycolysis without further activating oxida-
tive metabolism (Warburg, 1956). An improved understanding
of the mechanisms that regulate stem cell physiology would not
only improve our understanding of tissue homeostasis but also
would likely yield new therapeutic strategies for cancer.
B.P.L. was supported by an Irvington Institute-Cancer Research Institute/
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