Cell Turnover and Adult Tissue Homeostasis: From Humans To Planarians

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Cell Turnover and Adult Tissue Homeostasis: From Humans to

Planarians
Article in Annual Review of Genetics · February 2007

DOI: 10.1146/annurev.genet.41.110306.130244 · Source: PubMed
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Cell Turnover and Adult

Tissue Homeostasis: From
Humans to Planarians
Annu. Rev. Genet. 2007.41:83-105. Downloaded from arjournals.annualreviews.org
Jason Pellettieri and Alejandro Sánchez Alvarado

by University of Utah - Marriot Library on 12/27/07. For personal use only.
Howard Hughes Medical Institute, University of Utah School of Medicine,

Department of Neurobiology and Anatomy, Salt Lake City, Utah 84132-3401;
email: jpellett@neuro.utah.edu, sanchez@neuro.utah.edu
Annu. Rev. Genet. 2007. 41:83–105 Key Words

The Annual Review of Genetics is online at stem cells, cell death, apoptosis, self-renewal, regeneration
http://genet.annualreviews.org
This article’s doi: Abstract

10.1146/annurev.genet.41.110306.130244
Many fully developed metazoan tissues remain in a state of flux
Copyright c 2007 by Annual Reviews. throughout life. During physiological cell turnover, older differen-
All rights reserved
tiated cells are typically eliminated by apoptosis and replaced by the
0066-4197/07/1201-0083$20.00 division progeny of adult stem cells. Independently, each of these
processes has been researched extensively, yet we know very little
about how cell death and stem cell division are coordinated in adult
organs. Freshwater planarians are an attractive model organism for
research in this area. Not only do they undergo a very high rate
of somatic cell turnover throughout life, but experimental tools are
now available to study this process in vivo. Together, these attributes
provide an opportunity to investigate the mechanisms, functions,
and regulation of cell turnover in adult tissues.
83
INTRODUCTION has been estimated that each of us eradicates

and, in parallel, generates a mass of cells
. . . at least I know who I WAS when I got up this
equal to almost our entire body weight each
Tissue morning, but I think I must have been changed
homeostasis: the year (89). Thus, it is only through constant
several times since then. Alice, in Alice’s Ad-
maintenance of change that we in so many ways remain the
ventures in Wonderland, Lewis Carroll, 1865
normal tissue same.
(25).
morphology and The two basic parts of the cell turnover
function
“equation,” cell death and cell division, have
For many organisms, including humans, the
Cell turnover: a been researched and reviewed extensively
cycle of cell death relatively constant outward appearance of
over the past several decades. Although this
and rebirth that adult individuals belies an ongoing inner
contributes to an body of work has provided great insight into
transformation. In fact, it is this internal
organ’s normal tissue each of these individual processes, we know
change that paradoxically enables mainte-
homeostasis very little about how cell death is integrated
nance of the anatomical status quo, or tissue
Adult stem cells: with cell division, particularly during the self-
homeostasis. One critical mechanism preserv-
renewal of adult tissues. The purpose of this
cells in developed
ing form and function in developed tissues is
tissues that generate review then is to highlight several funda-
new stem cells as the conceptually straightforward yet poorly
mental, but largely unanswered, questions
well as daughters understood process of cell turnover. Simply
that will eventually about the regulation of cell turnover and its
stated, certain differentiated cells are regu-
differentiate role in fully developed organisms. We advo-
larly eliminated and replaced by the division
cate using the experimentally accessible fresh-
progeny of adult stem cells. In humans, the
water planarian Schmidtea mediterranea as a
magnitude of this flux is truly astounding—it
model system to begin addressing these ques-
tions. Before turning to these areas, how-
ever, we must first define some key terms
and review some basic concepts of adult tissue
dynamics.
CELL TURNOVER, TISSUE

HOMEOSTASIS, AND
REGENERATION
Differentiation Stem cell
division A wide variety of different processes, acting at
levels ranging from the molecular (e.g., DNA
repair) to the organismal (e.g., metabolism),
contribute to the preservation of anatomi-
cal form and function (85). For many meta-
Transient zoans, one of the most important means
amplification
of tissue homeostasis is the ongoing dele-
tion and replacement of certain differenti-
Figure 1
ated cells (Figure 1). We propose the term
A schematic model for cell turnover in a solid organ. The process begins
when a select cell is eliminated by apoptosis (top left). Blue fragments cell turnover for this process if it meets three
represent remnants of the apoptotic cell, which are eventually cleared by specific criteria: (a) there is a continual or
surrounding cells. Stem cells (lower right) divide to generate new stem cells periodic elimination of select differentiated
(circular black arrow) and cells that will go on to replace the eliminated cells from the tissue in question; (b) elim-
differentiated cell. This may or may not involve transient amplification of
inated cells are replaced through cell divi-
stem cell descendants (lower left; see text for details). Finally, a stem cell
descendant differentiates and replaces the eliminated cell (red arrows). The sion, typically involving adult stem cells and
process begins anew when another differentiated cell undergoes apoptosis their descendants; and (c) the newly generated
(upper right). Note that all of these processes are ongoing in vivo. cells differentiate and become functionally
84 Pellettieri · Sánchez Alvarado

integrated with the preexisting tissue. As Prevalence and Rates of Cell

discussed below, this definition is formally Turnover in Human Tissues
compatible with some developmental pro-
In contrast to the wholesale tissue replace- Self-renewal: the
cesses, but the primary focus of this re- ability of some
ment that occurs during regeneration, cell
view is on those cases of cell turnover that tissues to replace old
turnover is often difficult to detect, partic-
protect adult organisms from physiological and/or damaged cells
ularly when it occurs at a constant slow
dysfunction. through activation of
rate. Additionally, some of the experimental resident stem cell
Like cell turnover, regeneration is a form
tools that are used to document the occur- populations
of tissue replacement in which adult stem
rence of cell death and cell division in vivo Regeneration: the
cell populations respond, through unknown
[e.g., TUNEL (terminal deoxynucleotidyl replacement of
mechanisms, to the loss of specific cell types diseased or injured
transferase-mediated dUTP nick end label-
and initiate appropriate cell division and dif- body structures
ing) staining and BrdU (bromodeoxyuridine)
ferentiation programs. However, there is a TUNEL: terminal
labeling] can generate false-positive and false-
major distinction between these two phenom- deoxynucleotidyl

negative results. For these and other reasons,
ena. In most cases, regeneration is triggered
transferase-mediated
there is considerable debate about exactly
by a nonspecific pathological insult (e.g., in- dUTP nick end
where, when, and how much cell turnover oc- labeling
jury or disease) that removes or damages mul-
curs in adult mammalian tissues. It is widely
tiple types of tissue. Unlike the genetically BrdU:
accepted that self-renewal is a prominent fea- bromodeoxyuridine
programmed deletion of specific cells during
ture of the epidermis, intestine, lung, blood
physiological cell turnover, this often involves
and bone marrow, thymus, testis, uterus, and
an exogenous stimulus that causes acute dam-
mammary gland (13, 63). There are also at
age and provokes a strong inflammatory re-
least some data suggesting the occurrence of
sponse (e.g., wounding). The poor correla-
physiological cell turnover in the pancreas,
tion between the occurrence of normal cell
kidney, cornea, prostate, bone, adipose tissue,
turnover and the capacity for regeneration in
heart, and brain (3, 11, 13, 30, 63, 81). Al-
adult organs (85) may be partly attributable
though the details of adult tissue dynamics
to this difference. For instance, skeletal mus-
remain obscure or controversial in many of
cle has a strong regenerative potential, but the
these cases, it seems fair to conclude that hu-
satellite cells that confer this ability are qui-
man anatomy is far more dynamic than has
escent in the absence of acute injury (26). In
previously been appreciated.
light of these considerations, the mere pres-
The rate of cell turnover varies widely be-
ence of adult stem cells in a particular organ
tween organs. For example, it has been es-
is not sufficient to support a claim of ongoing
timated that the intestinal epithelium com-
cell turnover.
pletely self-renews within about 5 days,
whereas the epithelium in the lung takes up
CELL TURNOVER IN HUMAN to 6 months to be replaced (13). Moreover,
BIOLOGY cell turnover is an ongoing process in most or-
gans, but can sometimes occur in intermittent
Biologists have long recognized that tis-
cycles. The mammary gland, for instance, ex-
sues such as the skin, hematopoietic sys-
hibits cycles of growth and degeneration dur-
tem, and lining of the intestine undergo
ing the ovarian cycle as well as during preg-
rapid self-renewal and have a considerable
nancy and weaning (44).
regenerative capacity (55, 80), yet most
adult organs have historically been viewed
as strictly postmitotic. As described below, Functions and Medical Relevance
many biologists are now revisiting this as- of Cell Turnover
sumption in research with major clinical In addition to its general role in adult tissue
implications. homeostasis, cell turnover also contributes to
www.annualreviews.org • Cell Turnover 85

several tissue-specific functions. The ongoing MECHANISMS OF CELL

cell division and cell death in epithelial tissues TURNOVER
allows for maintenance of a barrier to envi- The three critical parameters governing adult
Apoptosis: a form
of cell suicide ronmental insults in the form of an outer layer tissue dynamics—cell death, cell division, and
characterized by of dead cells. In the brain, adult neurogene- cell differentiation—have been thoroughly
specific sis and cell death may be involved in learning analyzed in a wide variety of systems. Al-
morphological and memory (99, 102). And cell turnover in
features, such as though a full discussion of each of these topics
the uterus and mammary gland underlies pe- is beyond the scope of this review, some key
chromatin
condensation and riodic anatomical changes that are critical to concepts are discussed below, with an empha-
plasma membrane reproduction. sis on recent studies that have special rele-
blebbing Given the widespread occurrence of cell vance to cell turnover.
turnover in human tissues, it should come as
little surprise that this process is intimately
linked to human health. Aging and many

adult-onset diseases largely involve an imbal- Cell Death
ance between cell death and stem cell divi- In addition to its prominent role in devel-
sion. Conditions that exacerbate the rate of opment, cell death is indispensable for the
cell loss or impede the restorative action of proper function of many adult tissues. There
adult stem cell populations underlie degener- is a growing recognition that there are mul-
ative disorders and contribute to aging (95). tiple different ways for cells to die (33), but
Conversely, cancer can be attributed to fac- the two most well characterized forms of cel-
tors that tip the balance toward a net in- lular demise are necrosis and apoptosis. The
crease in cell number; namely, failure to en- former has classically been viewed as an ac-
gage cell death mechanisms in response to cidental form of death, though recent find-
genetic damage (41) and probably misregu- ings suggest it may be subject to a consider-
lated stem cell division (79). Indeed, when able degree of regulation (33). The latter is
oncogenic mutations induce pathological cell a form of cell suicide that is effected by evo-
proliferation, rapid tissue expansion is origi- lutionarily conserved molecular mechanisms
nally limited by a corresponding increase in involving the caspase family of cysteine pro-
cell death. It is only when this natural com- teases [for a review, see (28)]. The primary
pensatory mechanism is overcome by addi- distinction between necrosis and apoptosis
tional mutations that cancer progresses [see is the morphology of dying cells. Whereas
below and (41) for a full review]. Given these necrotic cells swell and burst, releasing their
considerations, there is significant interest in contents into the extracellular space and pro-
developing clinical treatments that might re- voking an inflammatory response, apoptotic
store the normal balance between cell death cells are neatly packaged into apoptotic bod-
and stem cell division in pathological con- ies that are phagocytosed by surrounding cells
texts. In the epidermis, for example, therapies (33).
that accelerate cell death may ameliorate the Apoptosis is widely cited as the primary
hyperplasia that accompanies psoriasis (54), means of cellular deletion during adult tissue
whereas enhancement of stem cells’ normal homeostasis. However, it is very difficult to
restorative capacity is a common goal in pro- investigate how cells die in an organ under-
moting wound healing (35, 60). The quest to going a low rate of physiological cell turnover
develop additional medical interventions for because cell death is a relatively rare event
conditions that disrupt normal cell turnover in this context. The notion of physiological
will undoubtedly benefit from an improved apoptosis in the heart, for instance, is very
understanding of the cellular and molecular controversial (3). At the other extreme, the
mechanisms that underlie this process. rapidity with which dying cells are shed from

highly proliferative tissues like the intestinal cells) can contribute to a variety of different
epithelium has also complicated mechanistic tissue lineages (104). In many instances, stem
analyses of cell death (51). Thus, the vast ma- cells divide only rarely and their descendants
Niches: cellular
jority of research in the cell death field to date undergo transient amplification prior to com- and/or extracellular
has focused on the more experimentally ac- mitting to a particular differentiation path- microenvironments
cessible contexts of development (e.g., em- way. This is one of several strategies that may that provide cues
bryogenesis in Caenorhabditis elegans) and the protect stem cells from replication-induced governing stem cell
behavior
response to various forms of stress or dam- mutations (23), but is clearly not an essen-
age (e.g., growth factor withdrawal or irradi- tial function as many stem cell populations
ation). One notable exception to this trend is divide throughout life and, in the case of
the large body of work dealing with cell death germline stem cells, can even be considered
in the immune system (61). However, apop- immortal.
tosis in cells such as lymphocytes may involve With respect to both regeneration and
specialized regulatory mechanisms that have physiological cell turnover, a key issue con-
limited relevance in other adult tissues. For cerns the regulation of stem cell division.
instance, signals from B cell and T cell recep- One critical parameter appears to be inter-
tors activate the core apoptotic machinery in actions between stem cells and their local
autoreactive lymphocytes during negative se- microenvironments, or niches. Both heterolo-
lection (61). Tissue-specific regulatory mech- gous cells and the extracellular matrix can pro-
anisms may also be involved in epithelial or- vide cues that regulate stem cell behavior. This
gans like the epidermis, where gradients of can entail signaling pathways [see (65) for re-
cell death gene expression are linked to the view], physical interactions, metabolic cues,
stratified morphology of the tissue (84). In and neural input (93). Well-characterized ex-
summary, there has been tremendous progress amples of stem cell niches are the germar-
in elucidating core molecular mechanisms of ial tip in the Drosophila ovary, the hub in
apoptosis in the past few decades, but many the Drosophila testis, the distal tip cell in the
specific questions about cell death in undam- germline of C. elegans, and the basement mem-
aged adult tissues remain unanswered. What brane of epithelial tissues (35, 60). In addition
are the initiating events that trigger cell death to extrinsic cues from the niche, stem cells
in this context? Is the “decision” to die cell- also rely on intrinsic programs to establish
autonomous or induced? And do dying cells and maintain their fates. In this regard, one
signal to stem cells to ensure their eventual area of significant current interest concerns
replacement? These questions are considered chromatin modifications in stem cells, such
in greater detail below. as those mediated by the Polycomb group
proteins (22).
Some tissues may be able to self-renew
Adult Stem Cells without enlisting stem cells. In these cases,
Stem cells are present in most, if not all, “self-duplication” of differentiated cells may
adult organs (82). During cell turnover, drive physiological turnover or even regener-
they serve as a reservoir for tissue renewal ation (31). For instance, β cells in the pan-
and repair, restoring differentiated cells that creas undergo self-duplication in the healthy
are eliminated by cell death. Somatic stem adult pancreas as well as in response to partial
cells are generally regarded as tissue-specific, pancreatectomy (30). Similarly, replication of
contributing solely to the maintenance of the mature hepatocytes drives regeneration of the
organ in which they reside. However, there is liver (100). Adult stem cells therefore play
evidence indicating that some stem cell pop- an important, but not universal, role in cell
ulations (most notably, hematopoietic stem turnover and regeneration.

Differentiation of Stem Cell types of cells are locally required and to mod-
Descendants ify the fate of their daughter cells accordingly
(76).
ISCs: intestinal Maintenance of adult tissues requires that
stem cells With respect to these and other signal-
newly generated cells adopt the appropriate
ing events, specific histological organizations
fate and contribute to the structure and func-
facilitate the interactions involved in cell
tion of the organ in which they reside. How,
turnover. For instance, epithelial tissues are
then, is the fate of stem cell division progeny
organized into structural-proliferative units,
determined? Displacement from the niche is
and this morphology is thought to influence
often an important starting point. For many,
multiple aspects of these tissues’ self-renewal
but not all, stem cells, the axis of cell division
(97). A similar situation is observed in the
is oriented perpendicular to the niche (70);
bone marrow, where the hematopoietic tis-
in this way, one daughter cell retains a stem
sue is organized in cords of cells grouped
cell fate through continued exposure to niche-
by lineage and localized between venous si-

derived signals, whereas displacement of the
nuses (sinusoids). Such cords are supported
other daughter away from the niche is permis-

by a meshwork of adventitial reticular cells be-
sive for differentiation or activates differenti-
lieved to provide the necessary microenviron-
ation programs by default. Examples of stem
ment to regulate hematopoietic processes (9).
and progenitor cells that fall into this cate-
gory are the germline stem cells in Drosophila
(60) and probably at least some of the pro-
liferating cells in the basal layer of stratified INTEGRATING CELL DEATH
epidermis (56). AND CELL DIVISION
Once removed from the niche, progen- Perhaps the most important questions con-
itor cells undergo differentiation according cerning cell turnover deal with the integra-
to intrinsic and/or extrinsic cues. In the for- tion of differentiated cell death and stem cell
mer category, unequal segregation of cell fate division. How is the proper balance struck
determinants prior to cell division may play between these counteracting processes, so
an instrumental role. This type of asymmet- that the size and morphology of higher-order
ric division has been thoroughly analyzed in structures (e.g., organs and organ systems) is
Drosophila neuroblasts. However, asymmetric maintained? Is there any communication be-
division is not a requisite trait of all stem cells, tween dying cells and adult stem cells? What
and many stem cell populations are likely to controls the overall rate of cell turnover? Ad-
alternate between symmetric and asymmetric dressing these issues presents a unique set of
modes of division in response to environmen- challenges, in that molecular mechanisms reg-
tal cues (70). ulating cell death and cell division must be
Extrinsic signals affecting progenitor cell linked to one another and studied both at the
differentiation emanate from a wide variety of level of individual cells and entire tissues. By
sources, including the niche, as noted above. exploiting powerful genetic approaches, de-
One surprising source of extrinsic signals has velopmental biologists have paved the way in
emerged from a recent study by Ohlstein & this area, yet it is important to recognize that
Spradling—stem cells themselves (76). In the fundamental differences exist between devel-
Drosophila midgut, intestinal stem cells (ISCs) oping and adult tissues. In this section, we
can generate two distinct differentiated cell summarize recent contributions to our knowl-
types, and it appears that the fate of ISC edge of developmental tissue dynamics before
daughters is determined by the level of Notch considering how these findings might inform
signaling from the ISC. In other words, these future studies of cell death and cell division in
stem cells may have a capacity to sense which adult organisms.

Cell-Autonomous Mechanisms Cell transformation requires not only mis-

Linking Cell Death and Cell Division regulated cell division, but also some block
to proliferation-induced sensitization to cell
The number of cells present in a tissue is 3 UTR: 3
death stimuli (41). untranslated region
a function of both the rate at which new
Subsequent studies have revealed many
cells are added and the rate at which exist-
other instances where genes coupling cell di-
ing cells are removed. A growing list of genes
vision and cell death have a major influence
has been shown to exert a coordinate influ-
on tissue dynamics. In Drosophila, elegant ge-
ence on both of these parameters in a cell-
netic mosaic screens have allowed for the
autonomous fashion. The prototype for this
identification and characterization of genes
class of molecules is c-myc, a gene encoding a
that cause dramatic tissue overgrowth when
transcription factor that regulates the expres-
mutated. Recently, several independent lines
sion of a large number of downstream target
of research have converged to reveal that
genes [reviewed in (73)]. c-myc was originally
a number of these genes act together in a

identified as a cellular homolog of the viral
common signaling pathway that simultane-
oncogene v-myc. Shortly thereafter, c-myc ac-

ously restricts cell proliferation and promotes
tivation was implicated in a wide variety of
apoptosis in developing epithelia [reviewed in
cancers and shown to be necessary for cell cy-
(32)]. Two cytoskeletal proteins, Merlin and
cle progression and sufficient to promote cell
Expanded, trigger this pathway in response
cycle reentry in quiescent cells. This evidence
to as-yet unknown signal(s) by stimulating a
pointed to the obvious conclusion that like
series of protein phosphorylation steps me-
most other known proto-oncogenes, c-myc
diated by the kinases Hippo and Warts and
regulated cell division (73). It came as some
the associated adaptor proteins Salvador and
surprise when c-myc expression was later ob-
Mats. The outcome of pathway activation is
served to trigger apoptosis in certain contexts
the phosphorylation and inhibition of a tran-
(4, 34). This finding led Evan et al. to propose
scriptional coactivator named Yorkie. In turn,
that c-myc’s seemingly conflicting roles reflect
this prevents expression of Yorkie target genes
a previously undetected connection between
that normally promote cell survival and pro-
the regulation of cell division and cell death.
liferation, including the cell cycle regulator
These researchers predicted that “successful
Cyclin E, the apoptosis inhibitor DIAP1, and
proliferation in normal cells requires the ac-
the microRNA bantam (32). Since bantam is
tive suppression of programmed cell death,
necessary for Yorkie-induced overprolifera-
thereby providing an inbuilt failsafe to guard
tion and sufficient to rescue yorkie mutant cells
against uncontrolled proliferation and so al-
from apoptosis (74, 101), inhibition of ban-
lowing the same basic machinery to regulate
tam expression is likely the key output of the
the two necessarily linked processes” (34). Ex-
Hippo pathway. How this translates into de-
perimental support for this hypothesis came
creased proliferation is not yet known, but
with the demonstration by Bissonnette et al.
the increase in apoptosis can be attributed to
that apoptotic cell death induced by c-myc can
bantam’s ability to represses expression of hid,
be inhibited by pro-survival factors such as the
a negative regulator of DIAP1, via bantam-
antiapoptotic protein Bcl-2 (12). This finding
complementary sites in the hid 3 UTR (18).
also explained the earlier observation by Vaux
and coworkers that bcl-2 and c-myc can syner-
gize to induce cell transformation (103). Over Cell-Nonautonomous Mechanisms
time, c-myc’s antagonistic pleiotropy, or simul- Linking Cell Death and Cell Division
taneous engagement of both cell prolifera- In addition to the intrinsic mechanisms dis-
tion and cell death mechanisms, has emerged cussed above, extracellular signals are also
as a recurring theme in cancer biology (41). known to exert a powerful influence on cell

fate in growing organisms. Two notable exam- family member Decapentapalegic (Dpp)
ples of such social control mechanisms (83) are and Wnt family member Wingless (Wg),
the phenomena of cell competition and com- play central roles. These secreted ligands
Dpp:
Decapentapalegic pensatory proliferation in the Drosophila wing are thought to function not only as a mor-
imaginal disc [reviewed in (36)]. The collec- phogens in the wing imaginal disc, but also as
Wg: Wingless
tive work of many investigators has revealed survival factors and mitogens, in part because
TGF-β:
that developing wing cells constantly moni- impairment of Dpp or Wg signaling leads to
Transforming
Growth Factor-β tor each other, adjusting their own behavior apoptosis of wing cells (2, 38) and increased
as well as that of their neighbors in response expression of either protein causes wing
to environmental perturbations. In this in- overgrowth (38, 57). One model for cell com-
stance, the key determinant of cell fate seems petition holds that the proliferating cells of
to be the rate of proliferation. Slower-growing the disc compete for limiting amounts of Dpp
cells are eliminated by apoptosis (cell com- protein; faster-growing clones capture and/or
petition), but apparently not before instruct- internalize higher amounts of the ligand
ing their neighbors to increase their own rate than slower-growing clones, which undergo
of growth and division in order to prevent a cell death as a result (Figure 2) (67). This
net reduction in cell number (compensatory model is based on several observations: (a)
proliferation). clones lacking the Dpp receptor Thickveins
Recent studies have provided some clues (Tkv) fail to proliferate and are eventually
about how these interactions might be medi- eliminated (21); (b) apoptosis can be induced
ated (Figure 2). Two signaling molecules, the by increasing the expression of brinker, a
Transforming Growth Factor-β (TGF-β) gene that is normally downregulated by Dpp
signaling (67); (c) the death of slower-growing
clones can be prevented by Dpp pathway
activation (66); and (d ) stimulation of endo-
Dpp cytosis in out-competed cells results in an
apparent increase in Dpp signal transduction
as well as a decrease in apoptosis (66). Two
studies also report that the fate of competing
cells is associated with the relative expres-
sion level of Dpp target genes, providing
?
added correlative data for this model (66,
JNK hid
67). However, another study reached the
Proliferation
opposite conclusion (29). There is also some
disagreement about exactly how apoptosis
Wg, Dpp Apoptosis is induced in out-competed cells (29, 66,
expression 67). Thus, future studies will be required to
resolve these discrepancies and to clarify the
Competitive cell Outcompeted cell exact mechanisms of cell competition.
Figure 2 Remarkably, dying cells appear to activate
A simple schematic model for cell competition and compensatory signaling pathways that promote the growth
proliferation in the Drosophila wing imaginal disc. Disc cells compete for of surrounding tissue prior to their demise
limiting amounts of Dpp (red ), with the “fittest” cells capturing and/or (Figure 2). Specifically, when apoptosis is in-
internalizing more Dpp ligand. Apoptosis is triggered in cells with duced in a clone of wing disc cells but then
reduced fitness through activation of the JNK pathway and/or increased
expression of the death-inducing gene hid (29, 66, 67). Prior to their
blocked at a downstream step in the cell death
elimination, apoptotic cells emit Dpp and/or Wg signals that trigger pathway, the resulting “undead” cells (and/or
compensatory proliferation in surrounding cells (blue arrow). Adapted their immediate neighbors) produce ectopic
from (36). Wg and Dpp proteins (49, 90). Ryoo et al.

went on to show that Wg signaling is neces- germ cells (PGCs) formed in the early em-
sary for the compensatory proliferation of sur- bryo proliferate to fill developing somatic
rounding viable cells (90). These researchers niches. Remarkably, the rate of PGC pro-
PGCs: primordial
also demonstrated that Wg and Dpp induc- liferation increases when embryos start out germ cells
tion still occurs when apoptosis is triggered with fewer PGCs, ensuring the eventual de-
ICs: intermingled
and then allowed to proceed normally. This velopment of fully fertile adults (37). A re- cells
argues against the possibility that the mito- cent study by Gilboa & Lehmann sheds light
genic effect of these molecules is an artifact on how the rate of PGC proliferation is
of experimental manipulations causing persis- controlled. PGCs signal to adjacent somatic
tence of cells normally fated to die (90). cells called intermingled cells (ICs) through
The developmental roles of cell competi- the EGF pathway. ICs depend on this sig-
tion and compensatory proliferation are not nal for their survival and undergo apoptosis
entirely clear. The studies referenced above if EGF signaling is inhibited. In turn, ICs in-
relied on experimental manipulations that hibit PGC proliferation through an unknown

greatly exaggerate differences in the rates of mechanism. These interactions form a self-
proliferation and/or apoptosis between mo- correcting feedback loop that tends toward
saic clones. It is not yet known to what ex- equilibrium (37). When PGC levels are de-
tent the resulting phenomena occur under creased, IC numbers also drop, relieving in-
normal circumstances. In response to abnor- hibition of PGC proliferation. Conversely,
mal conditions, however, the ability to dras- when PGC levels are elevated, IC numbers
tically alter rates of cell division and cell increase and PGC proliferation is decreased.
death with such precise spatial resolution pro-
vides obvious theoretical benefits (45). Most
notably, final organ size would be rendered Parallels and Differences Between
largely impervious to external influences. This Developing and Adult Tissues
particular theory is supported by two im- If the control of cell number during meta-
portant observations. First, blocking the cell zoan development is a longstanding biological
death pathways induced by cell competition or problem, the control of cell number in fully
the signaling pathways required for compen- developed tissues remains an even greater
satory proliferation leads to disc overgrowth puzzle. This can be attributed to many fac-
or undergrowth, respectively (29, 90). Sec- tors, not the least of which is the historical
ond, Drosophila growth regulators exhibit an emphasis on model organisms with life histo-
inverse correlation in their ability to induce ries favoring rapid development and high rates
cell competition and tissue overgrowth (45). of reproduction over adult tissue homeostasis.
Another possible function of social controls is As discussed above, geneticists are beginning
to act as a quality control mechanism ensuring to make significant inroads in the area of de-
that only the “fittest” cells contribute to the velopmental tissue dynamics using organisms
final organism (83). Notably, these beneficial like Drosophila. The question arises then as to
processes can also be turned to the detriment whether lessons learned using these systems
of an organism. Like other phenomena cou- can be extended to adult tissues. This question
pling cell death and cell division, cell compe- awaits a definitive answer, but it seems likely
tition and compensatory proliferation could that there will be some general commonalities
be hijacked as a precursor to tumorigenesis or as well as specific differences.
during cancer progression (66, 90). Perhaps the most significant distinction
Another elegant example of a system that between developing and adult tissues con-
couples cell death and cell division involves cerns the general degree of uniformity ob-
soma-germline interactions in the Drosophila served among constituent cells. In develop-
gonad. During larval growth, primordial ing systems such as Drosophila imaginal discs,

nearly all of the cells are dividing and can be (83). Another paradigm from developmental
eliminated by cell death if their rate of di- systems that could in theory apply to adult
vision differs substantially from that of their tissues is the release of signaling molecules
neighbors. In most adult systems, on the other by dying cells to alter the behavior of their
hand, only stem cells and their transiently neighbors. One attractive possibility is that
amplifying descendants undergo division and this not only regulates the rate of cell division,
cell death occurs in postmitotic differentiated as in compensatory proliferation, but also the
cells. By definition, strictly cell-autonomous fate of adult stem cell descendants. Accord-
controls cannot synchronize the behavior of ing to this scenario, dying cells could orches-
these distinct populations, arguing for the rel- trate their own replacement by directing stem
ative importance of cell-nonautonomous con- cells to generate precisely the correct number
trols in adult tissue homeostasis. Such extrin- and type of differentiated descendants.
sic mechanisms must be significantly different One final recurring theme likely to be en-
than those underlying developmental phe- countered in many adult tissues is the im-
nomena like cell competition. For example, portance of feedback loops like the one op-
the specific basis for cellular demise in com- erating in the Drosophila gonad (see above).
peting cells, a slow rate of division, has no rel- William Bullough hypothesized in 1962 that
evance for postmitotic cells in adult organs. secreted factors he called chalones might in-
Moreover, the coincidence of patterning and hibit the growth of the very organs that pro-
growth in developing tissues has allowed some duce them, thereby preventing unchecked or-
molecules like Dpp to be co-opted for use in gan enlargement (20). Nearly four decades
both processes. This duality might not apply later, experimental support for this hypothesis
to fully patterned adult tissues. surfaced with the identification of myostatin, a
Despite these and other differences, there mammalian member of the TGF-β superfam-
may be some general principles governing ily (62). This molecule is produced by adult
metazoan tissue dynamics throughout life. skeletal muscle, circulates in the blood, and
For example, the notion that cells might limits muscle fiber growth (58). A recent study
be subject to some form of competition as suggests that adult liver homeostasis and re-
a means of determining cellular “fitness” is generation is controlled by a similar mecha-
not unique to Drosophila. Competitive phe- nism of growth regulation. Bile acids are syn-
nomena have also been observed in the so- thesized from cholesterol in the liver, secreted
cial amoeba Dictyostelium discoideum (52), mice into the intestine to aid in lipid digestion, and
(77), and bacteria (39). And adult stem cells in then returned to the liver via the circulatory
the murine germline and hematopoietic sys- system. When liver function is compromised,
tem appear to compete for access to niches circulating bile acid levels become elevated.
(96, 98). Given the widespread occurrence Intriguingly, Huang et al. recently found that
of competition between individual cells or bile acid triggers liver regeneration in mice
groups of cells throughout evolution, it is pos- through activation of a nuclear receptor sig-
sible that these types of processes might con- naling pathway (48). This observation leads
trol cell number during adult cell turnover. to a simple model in which nuclear receptors
Martin Raff has proposed one such model: regulate liver size by sensing its functional ca-
“if a given level of survival factor supports a pacity. When liver injury or damage leads to
certain number of cells of a particular type, a bile acid buildup, these receptors promote
any increase of these cells above this num- liver growth until normal hepatic function is
ber would stiffen the competition and thereby restored and bile acid levels return to normal
tend to cause enough cells to die to return (48). In summary, although these mechanisms
the cell number to its original value; a fall do not link cell death and cell division like
in cell number would have the reverse effect” the developmental processes discussed above,

they do illustrate the pervasive role of feed- death. Methods for visualizing and manipu-
back loops throughout development and dur- lating both stem cell division and cell death
ing adult physiology. in vivo are discussed. We also consider rela-
H3P:
tionships between cell turnover and planari- phosphorylated
ans’ regenerative capacity and ability to sur- histone H3
CELL TURNOVER IN vive prolonged starvation.
PLANARIANS
Historically, the genetic analysis of model or-
ganisms has proven to be an invaluable ap- Neoblasts are Planarian Stem Cells
proach to uncovering the mechanisms of com- To date, the strongest evidence for the on-
plex biological processes. In the case of cell going turnover of adult planarian tissues has
turnover, however, there are important limi- come from studies of neoblasts [reviewed in
tations to today’s most prevalent experimen- (72)]. These cells have classically been de-
tal subjects. The adult soma of C. elegans and fined on the basis of their unique morphol-
Drosophila are largely postmitotic [with a few ogy, anatomical distribution, and mitotic ac-
notable exceptions, such as the Drosophila gut tivity (Figure 3). Specifically, they are small
(64, 75)]. And though vertebrate models do cells (approximately 5–10 μm in diameter)
show more extensive cell turnover, it is far that have a high nuclear-to-cytoplasmic ra-
more difficult to unambiguously identify and tio and lack the distinguishing features of
manipulate both adult stem cells and dying differentiated cell types (Figure 3a). They
cells in vivo in these systems. Indeed, the con- are distributed throughout the parenchyma,
troversy surrounding claims of cell turnover a mesodermal tissue that occupies the space
in such organs as the brain (40) and heart between the epidermis and the gut, and con-
(3) illustrates just how difficult it is to de- stitute ∼25–30% of all planarian cells (8).
termine whether this process occurs in many Unlike all differentiated cells in planarians,
vertebrate tissues, let alone how it is carried neoblasts remain mitotically active through-
out. out adult life (7). This has been demon-
In light of the above concerns, we pro- strated experimentally by specific labeling of
pose investigating the basic science of cell neoblasts with an antibody to a phosphory-
turnover in a favorite subject of early exper- lated form of histone H3 (H3P) that is used
imentalists: freshwater planarians. These an- as a mitotic marker in a wide range of or-
imals are free-living members of the phylum ganisms (71). Neoblasts can also be labeled
Platyhelminthes with bilateral symmetry and with the thymidine analog BrdU, which is in-
organ systems derived from all three germ lay- corporated into DNA during the S phase of
ers (72). Although they are most renowned the cell cycle (71). Importantly, if animals are
for their ability to regenerate complete ani- fixed and stained within 24 h of administering
mals from small body fragments [see below a pulse of BrdU, neoblasts are the only cell
and (88) for a full review], they also exhibit type labeled (Figure 3b). However, if animals
a high rate of cell turnover as part of their are fixed several days after BrdU administra-
normal tissue homeostasis. This is made pos- tion, labeled neoblast division progeny can be
sible by a mitotically active population of adult observed in postmitotic tissues such as the ep-
stem cells called neoblasts. In this section, we ithelium (Figure 4) (71, 87). In these cases,
review experimental evidence demonstrating neoblast descendants have adopted distinct
that neoblasts undergo continuous division in morphological features indicative of differen-
adult animals, that their division progeny dif- tiation. This observation is consistent with
ferentiate and are incorporated into postmi- previous reports demonstrating that neoblast
totic tissues, and that the resulting addition progeny can produce muscle (47, 69, 92),
of new cells is at least partly offset by cell rhabdite cells (46, 59), and germ cells (42).

a b 300 µm
Figure 3
Neoblasts are planarian stem cells that enable cell turnover in adult animals. (a) A transmission electron
micrograph of neoblasts near a wound site in S. mediterranea. The nuclei and cytoplasm of three
neoblasts are pseudocolored light red and green, respectively. A dying cell is evident in the lower right
corner (red arrow). Original magnification ∼10,000 × . (b) Neoblast division visualized in a
whole-mounted adult planarian by BrdU labeling. Animal was fixed and stained 8 h after exposure to
BrdU. Inset shows magnified view of boxed area. Adapted, with permission, from (71).
Since neoblast division and differentiation of Investigations of neoblast function provide

neoblast progeny occurs on an ongoing ba- further support for this conclusion. Because
sis, and in the absence of overall organismal they are the only dividing planarian cells,
growth, it is thought to reflect the occurrence neoblasts can be selectively destroyed by irra-
of physiological cell turnover. diation (10, 27, 87). This normally abolishes
long-term viability as well as regenerative ca-
pacity. In theory, these defects could be caused
6d Brdu cross section by damage to differentiated cells, but the ob-
servation that long-term viability and regen-
erative capacity can be restored by injection
of neoblasts isolated from unirradiated con-
trols argues against this possibility (8). Ge-
netic analyses provide further support for the
importance of the neoblast population in pla-
narian tissue homeostasis (see below).
The recent application of modern experi-
mental techniques to the study of planarians
promises to answer a number of longstand-
ing questions about neoblast biology. For ex-
ample, it is not yet known whether neoblasts
constitute a heterogeneous cell population.
10µm During regeneration, neoblasts and their di-
Figure 4 vision progeny can replace the 30–40 dif-
A differentiated, BrdU-labeled, neoblast descendant (white arrow) in the ferentiated cell types that are present in the
epidermis. Animal was fixed and stained 6 days after exposure to BrdU. adult organism [reviewed in (88)], demon-
Yellow lines denote the borders of the basement membrane. Adapted, strating their collective totipotence. Individu-
with permission, from (87). ally, however, there may be lineage-restricted

neoblast subpopulations. A related issue con- lencing phenomena (24) was recently iden-
cerns the possible existence of a transiently tified as an important regulator of neoblast
amplifying population of neoblast descen- function (87). This gene, called smedwi-2,
Totipotence: the
dants: It is unclear whether such a popula- is expressed primarily in dividing neoblasts, potential of a cell to
tion is present in adult animals or whether but appears to be required in neoblast de- give rise to all the
such a population arises temporarily during scendants. In smedwi-2 knockdown animals, differentiated cell
regeneration. Recent analyses of gene expres- neoblasts are still present and capable of ini- types that constitute
an adult organism
sion patterns in neoblasts and their division tiating a normal proliferative response after
progeny are likely to provide some insight wounding. Moreover, BrdU-labeled neoblast RNAi (RNA
interference) : a
in these areas (G. Eisenhoffer & A.S.A, un- progeny are capable of migrating into postmi-
gene silencing
published results). Additionally, we and oth- totic differentiated tissues. Notably, however, phenomenon in
ers are developing techniques for generating these cells fail to adopt a differentiated mor- which either
transgenic planarians, which would allow di- phology once they reach sites of cell turnover. endogenous or
foreign
rect visualization of neoblasts in live animals. This suggests that smedwi-2 does not function
double-stranded
This approach is likely to provide further in- in stem cell maintenance per se, but rather in
RNA molecules
sight into the degree of heterogeneity in the the generation of stem cell division progeny trigger the specific
neoblast population and could also be use- that are competent to replace differentiated degradation of
ful for discriminating between symmetric and cells during physiological cell turnover and homologous mRNAs
asymmetric modes of cell division. regeneration (87).
As noted above, niches provide an impor- A second gene involved in neoblast func-
tant element of control over adult stem cell tion was recently identified in an in situ hy-
behavior in many other organisms. It is not bridization screen for neoblast markers (43).
yet clear whether neoblasts reside within a bruli encodes a planarian member of the
niche, but recent data from our laboratory Bruno-like family of RNA binding proteins
have revealed that they frequently occupy nar- implicated in translational repression of spe-
row spaces between the branches of the gas- cific target mRNAs (105). Like smedwi-2, bruli
trovascular system (G. Eisenhoffer & A.S.A., is expressed in dividing neoblasts and is not re-
unpublished results). Thus, it will be intrigu- quired for neoblast proliferation in response
ing to learn whether these structures consti- to wounding. Unlike smedwi-2, however, bruli
tute a niche, an idea that is under current does not appear to be required for neoblast
investigation. descendants to differentiate and form postmi-
totic structures, at least during regeneration.
Instead, the primary defect in bruli knock-
Differentiation of Neoblast down animals is in neoblast maintenance. Be-
Descendants cause neoblast loss in adult animals lacking
The totipotence of the neoblast cell popu- bruli is gradual, in marked contrast to the rapid
lation raises two very important questions. elimination of neoblasts in response to irradi-
Do these cells “sense” which differentiated ation, Guo et al. propose that bruli may be
cell types have to be replaced during the required for neoblast self-renewal (43).
course of physiological cell turnover and re- Intriguingly, both smedwi-2 and bruli en-
generation? And how is the developmental code proteins predicted to function in post-
fate of neoblast daughter cells established? At transcriptional regulation of gene expression.
present, these questions remain unanswered, Reliance on these mechanisms has emerged
but two recent studies have provided some in- as a prominent feature of germ cells that
triguing clues. may play a fundamental role in their abil-
A planarian member of the PIWI/ ity to maintain a totipotent genome through
Argonaute gene family implicated in RNAi most of development (94). Thus, it is inter-
(RNA interference) and related mRNA si- esting to speculate that genes like smedwi-2

and bruli reflect the evolution of a similar for this prediction has been limited. Bowen,
strategy for regulating the fate of neoblasts Ryder, and coworkers conducted transmis-
and their descendants. For instance, Bruli may sion electron microscopy studies with the pla-
repress the translation of genes that induce narian Polycelis tenuis and reported ultrastruc-
differentiation, thereby promoting neoblast tural features consistent with cell death in
maintenance and/or self-renewal (43). And healthy adult animals (15–17), but it is not yet
SMEDWI-2 may enable rapid differentiation clear how prevalent this phenomenon is and
following cell cycle exit by inhibiting genes whether it represents apoptosis or some other
like bruli that normally keep differentiation form of cell death. Unfortunately, two recent
programs in check. Clearly, the identification investigations of cell death in planarians have
of downstream targets for these genes will be yielded ambiguous results. In one case, tech-
instrumental in testing such models. nical limitations in the detection of apoptotic
cells in Girardia tigrina precluded quantita-
tive analyses (19). The other report focused

Cell Death in Planarians
on a gene of Dugesia japonica misidentified as
The observation of ongoing neoblast divi- a caspase. The predicted protein for this gene
sion in nongrowing adult planarians has led lacks the invariant catalytic cysteine present
to the assumption that there is some form of in all known members of this protein fam-
cell death counterbalancing the resulting ad- ily (50). Hence, mechanistic analyses of cell
dition of new cells. However, direct support death in any planarian species are presently
lacking.
To fill this void, we recently established
a b
tools for visualizing and manipulating cell
death in the planarian S. mediterranea. Specif-
ically, we developed a TUNEL assay that la-
bels dying cells in whole-mounted animals
(Figure 5a) and used this assay to show that
RNAi-mediated silencing of cell death genes
alters the rate of cell death in vivo ( J.P., un-
published results). The approximate level of
cell death in adult animals, as determined by
TUNEL staining, is very close to the level
of neoblast division, as determined by H3P
staining (Figure 5b) ( J.P. unpublished re-
sults). This provides the first direct evidence
that cell death and stem cell division are at
or near equilibrium during physiological cell
turnover in adult planarians.
Although we have focused on the death of
differentiated cells in this review, cell death
could also play an important role in regulat-
ing adult stem cell populations (Figure 6).
200µm 500µm
Given the compelling evidence that stem cells
may be the “cells-of-origin” for many tumors
Figure 5 (79), apoptosis in mutant stem cells may be a
(a) Dying cells visualized in a whole-mounted adult planarian by TUNEL key safeguard against cancer (41). Cell death
staining. (b) Neoblast division visualized in a whole-mounted adult could also be important for the physiological
planarian by H3P staining. Image (b) courtesy of Carrie Adler. elimination of superfluous cells or stem cell

descendants that have adopted unnecessary or

inappropriate cell fates. These possibilities are
largely unexplored in adult stem cell popula-
tions, and it is not yet clear whether planarian
neoblasts undergo cell death on a regular ba-
sis. However, the development of TUNEL
staining and RNAi methods now makes it fea-
sible to address the specific issue of stem cell
death and also sets the stage for investigations
of cell death function and regulation in the
context of differentiated cell turnover.
Planarian Regeneration
and Degrowth
Planarians have attracted the interest of biol-

Figure 6
ogists for centuries, primarily because of their
Hypothetical models for cell death (dashed red Xs) in adult stem cell
remarkable anatomical plasticity. Thomas populations. Dividing stem cells, such as the planarian neoblast, can give
Hunt Morgan, the founder of Drosophila ge- rise to new stem cells (brown) or cells that will eventually differentiate (blue).
netics, researched planarian regeneration ex- Stem cell survival may be dictated by cell-autonomous factors, such as the
tensively prior to initiating his studies with level of myc expression, or extracellular signals derived from the niche. Stem
fruit flies. Among his many important find- cell-derived signals could also influence niche cell survival, as in the
Drosophila gonad (see text). The selective elimination of stem cell daughters
ings was that entire animals can be regen- would skew the population toward a particular fate, whereas elimination of
erated from body fragments approximately both daughter cells would reduce the overall size of the adult stem cell
1/300th an animal’s original size (68). The cel- population and the rate of cell turnover.
lular events involved in this process, which is
completed in just over a week in S. mediter- tal stimuli (injury, nutrient availability, etc.).
ranea, have been described in detail [see (88) Neoblast division is markedly upregulated
for a review]. However, the molecular mech- during the initial 6–12 h after wounding,
anisms regulating planarian regeneration are and this drives formation of the regenera-
not yet clear. tion blastema, a mass of undifferentiated tis-
In response to prolonged starvation, pla- sue at the wound site that will eventually re-
narians exhibit another striking form of place missing body structures [reviewed in
plasticity—the ability to “degrow” to less than (88)]. What stimulates this burst of division is
1/20th their original size (6, 78). This change unknown. Conversely, a decrease in neoblast
begins within a few weeks of food depriva- proliferation in response to starvation is one
tion and is reversed within a few days of feed- plausible way in which the net decrease in cell
ing. Degrowth results primarily from a change number might be effected during degrowth.
in cell number, rather than a change in cell There are conflicting reports on this matter
size (5, 6, 78), but the genes that respond to (5, 14), but H3P and BrdU labeling during
metabolic cues and regulate this process are degrowth should help to resolve the issue. As
unknown. for cell death, whether there are spatial and/or
One commonality between regeneration temporal changes in the elimination of stem
and degrowth must be some form of ad- and differentiated cell types from adult tissues
justment to the mechanisms regulating cell during regeneration or degrowth is unclear.
turnover in intact well-fed animals, so that Here again, the application of modern exper-
the ratio of dying cells to cells born by stem imental techniques, such as TUNEL staining,
cell proliferation is attuned to environmen- should provide some definitive answers.

Using Planarians to Test Models vide, generating additional descendants, they

of Adult Cell Turnover produce signals that activate cell death path-
ways in differentiated cells (Figure 7a, red
Planarians are now positioned as an ideal
arrows). By constantly monitoring which cell
model organism for systematic studies of
types they are eliminating, neoblasts can di-
cell turnover. Not only do they undergo a
rect the differentiation of their own descen-
high rate of physiological cell turnover as
dants accordingly (Figure 7a, blue arrow), en-
part of their normal tissue homeostasis, but
suring the swift replacement of deleted cells.
the H3P, BrdU, and TUNEL staining tech-
One prediction of this model is that disruption
niques described above allow for the in vivo
of neoblast division or function by irradiation
visualization of the cellular events that drive
or RNAi of genes such as bruli or smedwi-2
this process. Furthermore, these events can
would reduce, at least temporarily, the rate at
be manipulated by RNAi in adult organisms,
which differentiated cells are eliminated. This
causing specific adult tissue homeostasis
type of manipulation might ultimately result

phenotypes (86). A genome sequencing
in secondary effects, including an increase in
project for S. mediterranea, now nearing

the rate of cell death. Thus, it would probably
completion (1, 91), has greatly facilitated
be necessary to determine the rate of cell death
RNAi experiments, as well as microarray and
in RNAi animals at various timepoints after
in situ hybridization studies.
exposure to double-stranded RNA. A second
To illustrate how the planarian model sys-
prediction of this hypothesis is that neoblasts
tem can be used to dissect mechanisms regu-
and/or their division progeny should be in
lating cell turnover, we conclude by consider-
close proximity to dying cells. This could
ing a few hypotheses about how cell death and
be assessed by costaining wild-type animals
cell division might be coordinated. The mod-
with TUNEL and markers for neoblasts and
els outlined here are not mutually exclusive;
their division progeny, such as SMEDWI-
nor do they exclude other alternatives. These
2, Bruli, or monomethyl-K20 histone H4
models are presented simply to illustrate how
(43).
the development of new tools has empowered
An alternative to the model consid-
the pursuit of mechanistic insight into some
ered above is the cell death control model
of the more complicated areas of adult tissue
(Figure 7b), which predicts that the rate of
dynamics.
cell death is the primary determinant of the
As noted above, cell-nonautonomous
overall rate of cell turnover. In this case,
mechanisms are likely to play a particularly
the rate of cell death is set by mechanisms
important role in this area. In planarians, cell-
that act specifically on differentiated cells. In
cell signaling pathways could exert a major
turn, dying cells signal to neoblasts to regu-
influence on four key variables: (a) the death
late their rate of proliferation, in much the
of differentiated cells; (b) neoblast division;
same way that apoptotic cells activate com-
(c) the differentiation of neoblast descendants;
pensatory proliferation in Drosophila. Accord-
and (d ) neoblast cell death. Two speculative
ing to this hypothesis, one might expect that
models for the regulation of cell turnover in
inhibition of cell death would decrease the
adult planarians are presented in Figure 7
rate of neoblast division. This could be tested
(with the possibility of neoblast cell death
by using RNAi to target pro-death genes,
omitted for simplicity). According to the stem
followed by BrdU labeling or H3P stain-
cell control model (Figure 7a), the rate of
ing in RNAi animals. Conversely, increas-
neoblast division is set by a cell-autonomous
ing the rate of death by RNAi of prosur-
or neoblast-specific control mechanism that
vival genes might trigger increased neoblast
constitutes the primary determinant of the
division.
overall rate of cell turnover. As neoblasts di-

a Stem cell control model b Cell death control model
Dividing Dividing
neoblast neoblast
Doomed Dying
differentiated differentiated
cell cell
l n
na isio l
Differentiation
sig Div igna
ath s
De
signal
De Dif
ath fer
e
sig sig ntiat
nal na ion
l
Neoblast Neoblast
descendant descendant
Figure 7
Hypothetical models for cell-cell signaling during planarian tissue homeostasis. Any model for the
regulation of planarian cell turnover must address three key questions: 1. How are differentiated cells
fated to die? 2. How is the rate of neoblast proliferation controlled? 3. How is differentiation of neoblast
descendants regulated? Two hypothetical scenarios are depicted in (a) and (b). In each panel,
differentiated cells are represented by an epithelial cell (left). Neoblasts (brown) are small cells with large
nuclei that self-replicate and generate descendants (blue) that exit from the cell cycle and differentiate
(lower circular arrow). (a) Neoblast division is regulated cell-autonomously. Differentiated cells are
induced to die by signals from neoblasts (top red arrow), signals from neoblast division progeny (lower red
arrow), or failure to compete for limiting survival factors (yellow halo around neoblast). The fate of neoblast
descendants is determined by neoblasts themselves (vertical blue arrow). (b) The death of differentiated
cells is regulated cell-autonomously. Neoblast proliferation is triggered by signals from dying cells (purple
arrow). Dying cells also specify the fate of neoblast descendants (blue arrow).
CONCLUDING REMARKS death and stem cell division in adult model

In fully developed tissues, cell turnover typi- organisms. Planarians are an ideal choice in
cally involves the ongoing elimination of dif- this respect because they exhibit a high rate
ferentiated cells and their replacement by the of cell turnover throughout life made pos-
division progeny of adult stem cells. Along sible by a mitotically active and experimen-
with many other processes like DNA re- tally accessible population of pluripotent stem
pair, this plays an important role in tissue cells. Together with new tools for visualiz-
homeostasis, or the maintenance of anatomi- ing and manipulating the death of differenti-
cal form and function. Cell turnover can also ated cells, these characteristics form the basis
be observed in some developing tissues (see for impending hypothesis-driven experiments
above), but in this case, its primary function addressing the mechanisms and regulation of
is to ensure the robustness of developmen- adult tissue dynamics. These efforts should ul-
tal transitions (e.g., growth, patterning, and timately pay substantial dividends, as human
morphogenesis). This critical distinction il- cell turnover may be more widespread than
lustrates the importance of context: A more previously appreciated and is, in any case, fre-
thorough understanding of adult tissue re- quently altered as a precursor to adult-onset
newal will require in vivo analyses of both cell pathology.

SUMMARY POINTS
1. Cell turnover is a complex phenomenon that can be broken down into three integral
processes: (a) the elimination of select differentiated cells by genetically programmed
cell death; (b) the replacement of eliminated cells through cell division, typically
involving adult stem cells and their descendants; and (c) the differentiation of newly
generated cells and their integration with preexisting tissue.
2. Cell turnover is a key means of adult tissue homeostasis in many human organs. The
rate of cell turnover varies widely from one tissue to the next and can have special
functional significance in some tissues.
3. Defects in cell turnover underlie many adult-onset diseases, such as cancer and de-
generative disorders, and may also contribute to aging. A better understanding of the
basic science of normal adult tissue dynamics is likely to hasten the development of
effective medical interventions for these conditions.

4. Apoptosis underlies the selective elimination of old differentiated cells in many self-
renewing tissues. Important questions about the regulation of cell death in the context
of physiological cell turnover are largely unanswered.
5. Adult stem cells typically provide a source of new cells during cell turnover, but
differentiated cells can also meet this need in some organs. Both intrinsic and extrinsic
cues regulate stem cell division, as well as the division and differentiation of their
descendants.
6. The most significant gaps in our knowledge of cell turnover concern the integration
of cell death and stem cell division. Studies of phenomena such as cell competition
and compensatory proliferation in Drosophila have provided significant insight in this
area, yet major differences between developing and adult tissues necessitate additional
research on fully developed organisms.
7. Freshwater planarians represent an ideal model organism in which to study cell
turnover and its role in adult tissue homeostasis because: (a) they undergo a high
rate of cell turnover throughout life; (b) they possess a large and experimentally acces-
sible population of somatic stem cells; and (c) a wide variety of modern techniques can
now be applied to these animals, enabling mechanistic studies of stem cell division,
cell death, and the relationship between these processes.
DISCLOSURE STATEMENT
The authors are not aware of any biases that might be perceived as affecting the objectivity of
this review.
ACKNOWLEDGMENTS
J.P. is a fellow of The Jane Coffin Childs Foundation for Medical Research and thanks his daugh-
ter Grace and son Colin for alerting him to the quote from Alice’s Adventures in Wonderland and
for sacrificing bedtime stories while he was writing this review. A.S.A. is an investigator of the
Howard Hughes Medical Institute. We thank Carrie Adler, Kyle Gurley, and Voichita Mari-
nescu for their helpful comments on this manuscript, and apologize to the many researchers
whose work we were unable to cite because of space limitations.

LITERATURE CITED
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400:166–69
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Cell Turnover and Adult Tissue Homeostasis: From Humans to

Article in Annual Review of Genetics · February 2007

Jason Pellettieri Alejandro Sánchez Alvarado

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Cell Turnover and Adult

Jason Pellettieri and Alejandro Sánchez Alvarado

Howard Hughes Medical Institute, University of Utah School of Medicine,

Annu. Rev. Genet. 2007. 41:83–105 Key Words

This article’s doi: Abstract

INTRODUCTION has been estimated that each of us eradicates

CELL TURNOVER, TISSUE

84 Pellettieri · Sánchez Alvarado

integrated with the preexisting tissue. As Prevalence and Rates of Cell

major distinction between these two phenom- deoxynucleotidyl

www.annualreviews.org • Cell Turnover 85

several tissue-speciﬁc functions. The ongoing MECHANISMS OF CELL

linked to human health. Aging and many

86 Pellettieri · Sánchez Alvarado

www.annualreviews.org • Cell Turnover 87

by lineage and localized between venous si-

other daughter away from the niche is permis-

88 Pellettieri · Sánchez Alvarado

Cell-Autonomous Mechanisms Cell transformation requires not only mis-

a number of these genes act together in a

oncogene v-myc. Shortly thereafter, c-myc ac-

www.annualreviews.org • Cell Turnover 89

90 Pellettieri · Sánchez Alvarado

relied on experimental manipulations that hibit PGC proliferation through an unknown

www.annualreviews.org • Cell Turnover 91

92 Pellettieri · Sánchez Alvarado

www.annualreviews.org • Cell Turnover 93

Since neoblast division and differentiation of Investigations of neoblast function provide

94 Pellettieri · Sánchez Alvarado

www.annualreviews.org • Cell Turnover 95

tive analyses (19). The other report focused

96 Pellettieri · Sánchez Alvarado

descendants that have adopted unnecessary or

Planarians have attracted the interest of biol-

www.annualreviews.org • Cell Turnover 97

Using Planarians to Test Models vide, generating additional descendants, they

type of manipulation might ultimately result

project for S. mediterranea, now nearing

98 Pellettieri · Sánchez Alvarado

a Stem cell control model b Cell death control model

CONCLUDING REMARKS death and stem cell division in adult model

www.annualreviews.org • Cell Turnover 99

effective medical interventions for these conditions.

100 Pellettieri · Sánchez Alvarado

1. Washington Univ. Genome Sequencing Center. http://www.genome.wustl.edu/genome.

www.annualreviews.org • Cell Turnover 101

102 Pellettieri · Sánchez Alvarado

and adult rats.

www.annualreviews.org • Cell Turnover 103

belly spot and tail (Bst), a mouse Minute. Development 131:3907–20

regulation in the freshwater planarian Schmidtea mediterranea. Dev. Dyn. 226:326–33

104 Pellettieri · Sánchez Alvarado

neurogenesis in the adult hippocampus. Nature 415:1030–34

cooperates with c-myc to immortalize pre-B cells. Nature 335:440–42

www.annualreviews.org • Cell Turnover 105