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Cell biology of stem cells: an enigma of asymmetry and self-renewal
Haifan Lin1,2
1 Yale Stem Cell Center and 2 Department of Cell Biology, Yale
University School of Medicine, New Haven, CT 06511
Correspondence to Haifan Lin: haifan.lin@yale.
Stem cells present a vast, new terrain of cell biology. A central
question in stem cell research is how stem cells achieve asymmetric
divisions to replicate themselves while producing differentiated
daughter cells. This hallmark of stem cells is manifested either
strictly during each mitosis or loosely among several divisions.
Current research has revealed the crucial roles of niche signaling,
intrinsic cell polarity, subcellular localization mechanism,
asymmetric centrosomes and spindles, as well as cell cycle regulators
in establishing self-renewing asymmetry during stem cell division.
Much of this progress has benefited from studies in model stem cell
systems such as Drosophila melanogaster neuroblasts and germline stem
cells and mammalian skin stem cells. Further investigations of these
questions in diverse types of stem cells will significantly advance
our knowledge of cell biology and allow us to effectively harness
stem cells for therapeutic applications.
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Introduction: cell biology of asymmetry for self-renewal
Stem cells exist in early embryos and individual tissues. Embryonic
stem cells have the ability to ultimately differentiate into all
types of cells in our bodies, whereas tissue stem cells (also known
as adult stem cells) serve as immediate sources of cell supply to
their resident tissues. Stem cell research has offered the promise of
effective cell-based therapies in treating many debilitating diseases
such as diabetes, neurodegenerative diseases, and cancer. The
therapeutic potential of stem cells has inspired the imagination,
intense interest, and targeted investment of scientists, clinicians,
and the general public toward this fascinating area of biology. At
present, human embryonic stem cell research is politically charged,
with biologists engaging in ethical debates. Meanwhile, much of the
research effort has been channeled to harnessing stem cells into
desired cell types for clinical applications. Such translational
research has yielded some exciting results in tissue therapy by
transplantation. Excitement notwithstanding, there is still a long
way to go in understanding the fundamental mechanisms of stem cells
before new therapies will be effectively established. However, this
aspect of stem cell research has not garnered as much attention.
As evident from the three papers in this series of reviews, stem cell
biology is, by and large, an integral part of cell biology and
presents a vast new terrain of basic cell biology for exploration.
The hallmark of a stem cell is its ability to self-renew while
generating many daughter cells that are committed to differentiation.
Intimately related to this ability are a host of fundamental
questions that await investigation: How can we definitively identify
a stem cell? What defines a stem cell in molecular terms? What
signaling events control stem cell proliferation and differentiation?
How does a stem cell behave in its biological context? What happens
to a differentiated cell when it is reprogrammed into a stem cell or
vice versa? Solutions to these wide-ranging and perplexing questions
of cell biology are all related to understanding the single defining
feature of stem cells—their self-renewing ability. The self-renewing
ability of stem cells is tightly related to their ability to undergo
self-renewing asymmetric divisions. The concept of self-renewing
asymmetry should be applicable, either strictly during each mitosis
or loosely among several mitoses, to all types of tissue stem cells
and perhaps even to embryonic stem cells to account for their self-
renewal. A stereotypical asymmetric division gives rise to both a
daughter stem cell and a daughter cell that has acquired a more
differentiated fate. This unique asymmetry allows a stem cell to self-
replicate while producing numerous differentiated progeny. It is
distinct from another form of asymmetric division that produces two
daughter cells that are different from each other as well as from the
mother, as often seen for progenitor cells. For those stem cells that
undergo apparently symmetric divisions, the self-renewing asymmetry
still exists among several divisions because, even stochastically,
50% of the daughter cells need to acquire a more differentiated fate
after the divisions. Therefore, how the self-renewing asymmetry is
achieved is a central question in stem cell biology.
The three reviews in this issue effectively summarize the latest
progress in our understanding of mechanisms that underlie self-
renewing asymmetric division of three of the best-characterized
tissue stem cell systems—Drosophila melanogaster neuroblasts,
Drosophila germline stem cells, and mammalian skin stem cells.
Discoveries from these three model systems complement one another,
each revealing a unique aspect of the asymmetric mechanism. Together,
they present a comprehensive landscape of molecular mechanisms
underlying the self-renewing asymmetric division of stem cells. It is
a pleasure to comment on these exciting discoveries from a more
general perspective.
The niche induces asymmetric division
Self-renewing asymmetric division of a stem cell is controlled by
both extrinsic signaling and intrinsic mechanisms. Much progress has
been made in understanding intercellular mechanisms, especially the
identification of niches for various types of tissue stem cells and
elucidation of the role of the niche in regulating asymmetric stem
cell division. Perhaps the best-illustrated role of the niche in
regulating stem cell division comes from the study of germline stem
cells in the Drosophila ovary and testis (see Yamashita and Fuller on
p. 261 of this issue; for more detailed information, also see Lin,
2002). In female flies, somatic niche signaling requires the TGFâ
pathway and another signaling pathway defined by the YB and PIWI
proteins, which are required in niche cells for germline stem cell
maintenance. The TGFâ and YB–PIWI pathways converge in germline stem
cells to repress the expression of bag of marbles (bam), a gene that
is necessary and sufficient for promoting stem cell differentiation
(Chen and McKearin, 2005; Szakmary et al., 2005). The niche function
is also assisted by Hedgehog signaling and requires niche cell–stem
cell adhesion as mediated by epithelial cadherin (King et al., 2001;
Song et al., 2002). The niche induces the attachment of one pole of
the stem cell spindle to the niche cells (Deng and Lin, 1997). Such
attachment is mediated by a spectrin-rich structure called the
spectrosome and a cytoplasmic dynein-mediated mechanism (Deng and
Lin, 1997; McGrail and Hays, 1997).
Similarly, the Drosophila male germline stem cell system contains
somatic niche cells (hub cells) that secrete the unpaired ligand for
the JAK–STAT (Janus kinase–signal transducer and activator of
transcription) signaling pathway to maintain germline stem cells, as
reviewed by Yamashita and Fuller (2008). As a stem cell divides, one
pole of its mitotic spindle is anchored to the niche cells, ensuring
the asymmetric division that allows only one of the two daughter
cells to maintain contact with the niche cells and, as such, retains
the stem cell fate. This attachment requires adherens complexes that
contain cadherin, â-catenin, and adenomatous polyposis coli 2 (APC2)
protein, which is similar to the anchorage of mitotic spindle in
Drosophila embryonic epithelial cells (for review see Lin, 2003).
Although the role of niche in the asymmetric division of mammalian
stem cells has not been as clearly illustrated, Fuchs and colleagues
have shown that embryonic basal epidermal cells use their polarity to
divide asymmetrically with respect to the underlying basal lamina,
generating a committed suprabasal cell and a proliferative basal cell
(Lechler and Fuchs, 2005; see Fuchs on p. 273 of this issue). Because
skin stem cells are a subpopulation of mitotically active basal
epidermal cells, it is conceivable that these stem cells divide in an
asymmetric fashion to self-renew and to produce differentiated
keratinocytes. Moreover, integrins and cadherins in the basal lamina
are essential for the proper localization of apical complexes
containing atypical PKC (aPKC), the Par3–LGN–Inscuteable protein, and
NuMA (nuclear mitotic apparatus protein)–dynactin. This asymmetric
localization may be functionally important because similar complexes
in Drosophila neuroblasts are essential for asymmetric division, as
reviewed in this issue (see Chia et al. on p. 267 of this issue). The
requirement of integrins and cadherins suggests that the
extracellular matrix, such as basal lamina, can also serve as a stem
cell niche or part of a niche. Such an acellular niche also contains
signaling molecules such as laminin 5, which is a stable ligand for
integrin in hemidesmosomes and focal adhesions. In addition, the
basal lamina may serve as mechanical support to the stem cell system.
Moreover, its resident proteoglycans and other proteins may function
as molecular sinks for growth factors that either promote or restrict
the proliferation of epidermal cells, thus serving as a signaling
source for these molecules.
In addition to basal epidermal cells, mouse neuroepithelial stem
cells and hematopoietic precursor cells undergo both asymmetric and
symmetric divisions. In the mammalian central nervous system,
embryonic neuroepithelial cells first undergo symmetric division to
expand their population and then switch to asymmetric divisions for
neurogenesis. This switch involves a change in cleavage plane
orientation from perpendicular to parallel to the plane of the apical
lamina, leading to an asymmetric distribution to the daughter cells
of the apical plasma membrane, which constitutes only a minute
fraction (1–2%) of the entire neuroepithelial cell plasma membrane
(Kosodo et al., 2004). Somewhat similarly, mouse hematopoietic
progenitor cells are capable of both symmetric and asymmetric
divisions in cultures supported by stromal cells (Wu et al., 2007). A
prodifferentiation stromal cell line increased the frequency of
asymmetric division, whereas a pro-proliferation stromal cell line
promoted symmetric division. These observations indicate that niche
signaling can also control the asymmetry of stem cell division at a
populational level.
Inherited cell polarity determines asymmetric division
Although niche induction accounts for asymmetric division in some
types of stem cells, it may not play a role in all types of stem
cells. For Drosophila neuroblasts, the initial cue for symmetry seems
to depend solely on the cell itself, as reviewed by Chia et al.
(2008). The neuroblasts are derived from embryonic epithelial cells
and inherit their polarity, with one end being apical and the other
being basal. This allows molecules that determine cell fate to be
segregated along the apical-basal axis. The mitotic spindle is also
oriented along this axis such that the plane of division is
perpendicular to the axis. This means that one daughter cell inherits
the apical molecules and remains a neuroblast; the other inherits the
basal components and becomes a ganglion mother cell.
Studies on Drosophila neuroblasts in the past 15 years have
identified a group of proteins localized to the apical cortex that
determine the asymmetry of stem cell division. These proteins are
organized into two complexes linked by the Inscuteable protein. The
first complex includes Bazooka–Par3, aPKC, and Par6, which regulates
the tumor suppressor Lethal (2) giant larva (LGL). Such regulation is
likely via phosphorylation, which, in turn, affects the activity of
LGL in the localization of basal complexes. Conversely, LGL inhibits
the basal localization of aPKC, thereby restricting aPKC to the
apical cortex (Lee et al., 2006). Therefore, the regulation of LGL
and aPKC is likely to be mutual inhibition. The second apical complex
contains heterotrimeric G protein signaling mechanism components: Gi,
Partner of Inscuteable (Pins), and Locomotion defect (Loco). These
two complexes work in parallel to control the asymmetric localization
of cell fate regulators, the apicobasal orientation of the mitotic
spindle, and the asymmetric structure of the spindle itself. The
coordination of all of these aspects of asymmetry is essential for
the asymmetric fates of the two daughter cells, as reviewed by Chia
et al. (2008), and will be discussed in further detail in the
following sections.
Interestingly, key components of the Par3 complex have also been
found in the apical cortex of mammalian skin stem cells, as reviewed
by Fuchs (2008). The mouse Numb homologue is localized asymmetrically
during hematopoietic precursor cell division, similar to the
asymmetric behavior of Numb in Drosophila neuroblasts (Wu et al.,
2007). These observations raise the possibility that the asymmetric
mechanism discovered in the Drosophila neuroblast is conserved during
evolution.
Centrosomal asymmetry contributes to asymmetric division
A fundamental aspect of the asymmetric division mechanism is the
asymmetric property of centrosomes during stem cell division. The
mother and daughter centrosomes are known to differ in size,
molecular composition, the ability to organize microtubules, and even
the ability to localize mRNAs or possibly other cell fate
determinants, as systematically discussed by Yamashita and Fuller
(2008) and by Chia et al. (2008). In both Drosophila male germline
stem cells and neuroblasts, the large mother centrosome organizes a
more extensive population of astral microtubules and is selectively
retained in the daughter stem cell after stem cell division. This
feature has also been found in mammalian cultured cells.
Additionally, the two centrosomes may differentially associate with
cell fate determinants, which would be an effective mechanism for the
asymmetric segregation of cell fate determinants. Finally, anchoring
of the mother centrosome to the niche is also important for the
oriented asymmetric division.
The multifaceted difference between the mother and daughter
centrosomes may be a consequence of the structural difference of
their resident old and young centrioles, as discussed by Yamashita
and Fuller (2008). The exploration of asymmetric features in
centrosomal biogenesis and function represents a new area of stem
cell research with general implications in cell and cancer biology.
Spindle asymmetry determines the size difference of the two daughter
cells
An intriguing feature of asymmetry as revealed by the study of
Drosophila neuroblast division is the asymmetric geometry of the
mitotic spindle. Particularly, the distance between the apical pole
and equator of the spindle is greater than that between the basal
pole and the equator. This results in an apically located larger
daughter neuroblast and a basally located smaller differentiated cell
(i.e., the ganglion mother cell). The spindle asymmetry is controlled
by both apical complex I (Bazooka–Par3 and aPKC–Par6) and apical
complex II (Gi–Pins–Loco)
to maintain the geometric asymmetry of the spindle (Cai et al.,
2003). In addition, the apical localization of these complexes leads
to displacement of the spindle toward the basal cortex, which also
contributes to the size difference between the two daughter cells.
Given that the components of these complexes are evolutionally
conserved, this mechanism may be involved in the asymmetric division
of other types of stem cells that generates two daughter cells of
unequal size.
Cell cycle regulators have novel roles in asymmetric division
A particularly exciting development in basic stem cell research in
the past few years is the discovery of novel functions of cell cycle
regulators in controlling the asymmetry of stem cell division, as
timely reviewed by Chia et al. (2008). For example, the CDC2/CDK1
level controls whether a neural or muscle progenitor undergoes
symmetric or asymmetric division. In neuroblasts, high levels of CDK1
during mitosis are required for the asymmetric localization of apical
and basal protein complexes. In addition, Aurora and Polo kinases act
as tumor suppressors in neuroblasts by preventing excess self-
renewal, implicating the function of asymmetric division in
restricting overproliferation. The mutations of these two kinase
genes affect the asymmetric localization of aPKC, Numb, Partner of
Numb, and Notch, causing symmetric division to generate two daughter
neuroblasts. In addition, anaphase-promoting complex/cyclosome is
also required for the localization of Miranda and its cargo proteins
(Prospero, Brain Tumor, and Staufen). More surprisingly, even cyclin
E, a G1 cyclin, is involved in asymmetric neuroblast division.
Multiple lines of evidence suggest that the asymmetric function of
these cell cycle regulators is not via their conventional function in
cell cycle control but rather by directly impinging on the asymmetric
localization and segregation machineries in neuroblasts. Mutants of
some of these cell cycle genes exhibit tumor phenotypes, which is
similar to the phenotype of genes required for apicobasal polarity in
Drosophila epithelia and neuroblasts. These observations highlight
the importance of asymmetry in preventing overproliferation (Chia et
al., 2008).
Asymmetric division and tissue maintenance: skin as an example
Just as it is important to understand the asymmetric mechanism of
stem cells, it is imperative to comprehend the biological impact of
asymmetric stem cell division on the development and maintenance of
tissues. In this regard, mammalian epidermal stem cells provide an
unparalleled opportunity. As described in the review by Fuchs (2008),
stem cells for the epidermis and its appendages (hair follicles and
sebaceous glands) have been relatively well identified. In the
epidermis, different types of differentiating keratinocytes are
organized in an orderly fashion along the baso-apical axis. This
reflects a gradient of differentiation from basally located stem
cells to the most differentiated cells, the stratum corneum on the
apical surface. This organization pattern is readily accessible for
investigating how the asymmetric division of epidermal stem cells
with a defined orientation serves the need to replenish this tissue.
Moreover, epidermal stem cells together with hair follicle and
sebaceous gland stem cells contribute to the skin. The three types of
stem cells behave similarly in their corresponding lineage, yet they
can transiently contribute to another lineage during the injury
repair process. This provides excellent opportunities for studying
the coordinated control of different stem cell lineages within a
tissue to ensure its development and homeostasis. For example, Wnt
signaling plays a key role in promoting hair follicle versus
epidermal development. After formation of the hair follicle
primordial (placodes), Shh further promotes the growth and maturation
of hair buds by turning on specific transcription factors. Fuchs
(2008) elegantly addresses these issues.
Concluding remarks
Current progress in studying the self-renewing mechanisms of stem
cells demonstrates how basic stem cell questions are
characteristically cell biological questions and how these questions
can be effectively approached by cell biological approaches. Current
findings also reveal that stem cells use evolutionally conserved
molecular pathways and machineries for their asymmetric division and
self-renewal. Thus, the unique properties of stem cells are more a
result of the unique combination of cell-general mechanisms than the
existence and effect of stem cell–specific molecules. The three
reviews in this issue each in its own unique way cover this exciting
progress as well as present challenging questions that await
exploration. These challenges and progress invite cell biologists to
the fascinating world of basic stem cell research.
Acknowledgments
I thank Valentina Greco, Travis Thomson, Li Liu, Xiao Huang, and
Jianquan Wang for critical reading of this review.
The stem cell work in my laboratory is supported by the National
Institutes of Health (grants HD33760, HD42042, and HD37760S1), the
Connecticut Stem Cell Research Fund, the G. Harold and Leila Mathers
Award, and the Stem Cell Research Foundation.
Submitted: 27 December 2007
Accepted: 7 January 2008
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Related Articles
Asymmetric centrosome behavior and the mechanisms of stem cell
division
Yukiko M. Yamashita and Margaret T. Fuller
J. Cell Biol. 2008 180: 261-266. [Abstract] [Full Text]
Drosophila neuroblast asymmetric divisions: cell cycle regulators,
asymmetric protein localization, and tumorigenesis
William Chia, W. Gregory Somers, and Hongyan Wang
J. Cell Biol. 2008 180: 267-272. [Abstract] [Full Text]
Skin stem cells: rising to the surface
Elaine Fuchs
J. Cell Biol. 2008 180: 273-284. [Abstract] [Full Text]
Published online 28 January 2008
doi:10.1083/
The Journal of Cell Biology, Vol. 180, No. 2, 257-260
© The Rockefeller University Press, 0021-9525 $30.00
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