The centrosome and asymmetric cell division

Asymmetric stem cell division is a mechanism widely employed by the cell to maintain tissue homeostasis, resulting in the production of one stem cell and one differentiating cell. However, asymmetric cell division is not limited to stem cells and is widely observed even in unicellular organisms as well as in cells that make up highly complex tissues. In asymmetric cell division, cells must organize their intracellular components along the axis of asymmetry(sometimes in the context of extracellular architecture). Recent studies have described cell asymmetry in many cell types, and in many cases such asymmetry involves the centrosome (or spindle pole body in yeast) as the center of cytoskeleton organization. In this review, I summarize recent discoveries in cellular polarity that lead to an asymmetric outcome, with a focus on centrosome function.     

The centrosome and asymmetric cell division

Asymmetric stem cell division is a mechanism widely employed by the cell to maintain tissue homeostasis, resulting in the production of one stem cell and one differentiating cell. However, asymmetric cell division is not limited to stem cells and is widely observed even in unicellular organisms as well as in cells that make up highly complex tissues. In asymmetric cell division, cells must organize their intracellular components along the axis of asymmetry (sometimes in the context of extracellular architecture). Recent studies have described cell asymmetry in many cell types and in many cases such asymmetry involves the centrosome (or spindle pole body in yeast) as the center of cytoskeleton organization. In this review, I summarize recent discoveries in cellular polarity that lead to an asymmetric outcome, with a focus on centrosome function.Key words: stem cell, asymmetric division, niche, centrosome, spindle orientation     

Polarization and asymmetric division of stem cells

Asymmetric cell division observed in many groups of organisms has similar mechanisms suggesting conservatism of the process. Asymmetric division of stem cells that reside in their niches is aimed to regulation of cell proliferation and genome stability maintenance. But stem cells may also divide symmetrically depending on situation. Alteration of mechanisms of asymmetric division might be one of the factors of neoplasm growth.     

多细胞生物干细胞不对称分裂的内在调节机制研究进展

多细胞生物的发育是从一个受精卵分化成多种类型细胞的过程。细胞多样性形成的基础是不等分裂,不等分裂是干细胞自我更新和自我维持的关键。干细胞不等分裂有细胞内和细胞外两种调节机制。果蝇神经干细胞增殖和分化、植物胚胎发育、表皮气孔形成及根内皮层的分化,是研究不等细胞分裂调节机制最多的发育背景。本综述介绍了果蝇神经干细胞和植物胚胎发育早期、表皮气孔发生及根皮层内皮层中细胞不等分裂内在调节机制的研究进展。     

Biophysical factors in the regulation of asymmetric division of stem cells

Stem cells are a promising cell source for regenerative medicine due to their characteristics of self‐renewal and differentiation. The intricate balance between these two cell fates is maintained by precisely controlled symmetric and asymmetric cell divisions. Asymmetric division has a fundamental importance in maintaining tissue homeostasis and in the development of multi‐cellular organisms. For example, during development, asymmetric cell divisions are responsible for the formation of the body axis. Mechanistically, mitotic spindle dynamics determine the assembly and separation of chromosomes and regulate the orientation of cell division. Interestingly, symmetric and asymmetric cell division is not mutually exclusive and a range of factors are involved in such cell‐fate decisions, the measurement of which can provide efficient and reliable information on the regenerative potential of a cell. The balance between self‐renewal and differentiation in stem cells is controlled by various biophysical and biochemical cues. Although the role of biochemical factors in asymmetric stem cell division has been widely studied, the effect of biophysical cues in stem‐cell self‐renewal is not comprehensively understood. Herein, we review the biological relevance of stem‐cell asymmetric division to regenerative medicine and discuss the influences of various intrinsic and extrinsic biophysical cues in stem‐cell self‐renewal. This review particularly aims to inform the clinical translation of efforts to control the self‐renewal ability of stem cells through the tuning of various biophysical cues.     

From endocytosis to tumors through asymmetric cell division of stem cells

Recent studies in vertebrate and invertebrate model organisms uncover the importance of endocytosis for biased signaling during asymmetric cell division. In stem cells, perturbing polarity and asymmetric division affect their selfrenewal causing exponential proliferation, thereby giving rise to cancer. An emerging pattern is that endocytosis controls asymmetric cell division, which underlies stem cell selfrenewal and defective selfrenewal is on the basis of tumorigenesis caused by cancer stem cells.     

Regulation of mouse spermatogonial stem cell self-renewing division by the pituitary gland

Spermatogenesis originates in spermatogonial stem cells, which have the unique mode of replication. It is considered that a single stem cell can produce two stem cells (self-renewing division), one stem and one differentiating (asymmetric division), or two differentiating cells (differentiating division). However, little is known regarding how each type of division is regulated. In this investigation, we focused on the analysis of self- renewing division and examined the effect of the pituitary gland using two models of stem cell self-renewing division. In the first experiment using newborn mice, the administration of GnRH- analogue, which represses the release of gonadotropin, reduced the number of stem cells during postnatal testicular development, suggesting that the pituitary gland enhances stem cell self- renewing division. In the second experiment, however, the number of stem cells increased dramatically in hypophysectomized adult recipients after spermatogonial transplantation. Thus, the pituitary gland affects the self-renewing division of stem cells, but these contradictory results suggest that its role may be different depending on the stage of the testicular development.     

piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells

piwi represents the first class of genes known to be required for stem cell self-renewal in diverse organisms. In the Drosophila ovary, piwi is required in somatic signaling cells to maintain germline stem cells. Here we show that piwi encodes a novel nucleoplasmic protein present in both somatic and germline cells, with the highly conserved C-terminal region essential for its function. Removing PIWI protein from single germline stem cells significantly decreases the rate of their division. This suggests that PIWI has a second role as a cell-autonomous promoter of germline stem cell division. Consistent with its dual function, over-expression of piwi in somatic cells causes an increase both in the number of germline stem cells and the rate of their division. Thus, PIWI is a key regulator of stem cell division - its somatic expression modulates the number of germline stem cells and the rate of their division, while its germline expression also contributes to promoting stem cell division in a cell-autonomous manner.     

Chlamydia trachomatis inclusions induce asymmetric cleavage furrow formation and ingression failure in host cells

Chlamydia trachomatis infection has been suggested to induce host genome duplication and is linked to increased risks of cervical cancer. We describe here the mechanism by which Chlamydia causes a cleavage furrow defect that consistently results in the formation of multinucleated host cells, a phenomenon linked to tumorigenesis. Host signaling proteins essential for cleavage furrow initiation, ingression, and stabilization are displaced from one of the prospective furrowing cortices after Chlamydia infection. This protein displacement leads to the formation of a unique asymmetrical, unilateral cleavage furrow in infected human cells. The asymmetrical distribution of signaling proteins is caused by the physical presence of the Chlamydia inclusion at the cell equator. By using ingested latex beads, we demonstrate that the presence of a large vacuole at the cell equator is sufficient to cause furrow ingression failure and can lead to multinucleation. Interestingly, internalized latex beads of similar size do not localize to the cell equator as efficiently as Chlamydia inclusions; moreover, inhibition of bacterial protein synthesis with antibiotic reduces the frequency at which Chlamydia localizes to the cell equator. Together, these results suggest that Chlamydia effectors are involved in strategic positioning of the inclusion during cell division.     

Asymmetrical cell division in Blepharisma japonicum: difference between daughter cells in mating-type expression

In cell division of high-frequency-selfers in the ciliate Blepharisma japonicum, daughter cells are different in mating-type expression. The anterior daughter cell is mating type I. The posterior daughter cell is mating type II at first and then changes to mating type I after about 24 h. The anteroposterior polarity of predivision cells appears to correlate with the asymmetrical cell division. This work introduces a unicellular organism about the size of microscopic metazoa as a model system for the study of asymmetrical cell division, which is particularly important in developmental processes.     

Contrasting mechanisms of stem cell maintenance in Drosophila

Stem cells are self-renewing multipotent cells essential for development or homeostasis of many tissues. Stem cell populations can be found in most multicellular plants and animals. The mechanisms by which these populations are maintained are diverse, utilizing both intrinsic and extrinsic factors to regulate cell division and differentiation. The genetic tools of the fruitfly, Drosophila melanogaster, have permitted detailed characterization of two stem cell populations. In this review, we will examine these contrasting stem cell model systems from Drosophila and their relevance to stem cell populations in other organisms.     

Germline stem cells

Sperm and egg production requires a robust stem cell system that balances self-renewal with differentiation. Self-renewal at the expense of differentiation can cause tumorigenesis, whereas differentiation at the expense of self-renewal can cause germ cell depletion and infertility. In most organisms, and sometimes in both sexes, germline stem cells (GSCs) often reside in a defined anatomical niche. Factors within the niche regulate a balance between GSC self-renewal and differentiation. Asymmetric division of the germline stem cell to form daughter cells with alternative fates is common. The exception to both these tendencies is the mammalian testis where there does not appear to be an obvious anatomical niche and where GSC homeostasis is likely accomplished by a stochastic balance of self-renewal and differentiation and not by regulated asymmetric cell division. Despite these apparent differences, GSCs in all organisms share many common mechanisms, although not necessarily molecules, to guarantee survival of the germline.     

Sirt1, Notch and stem cell "age asymmetry"

Almost all complex multicellular organisms on earth utilize oxygen for the production of energy. This strategy carries the risk for damaging ROS to be generated and so these biochemical pathways must be highly regulated. Because of this, regulation of oxidative-phosphorylation is tightly coordinated with every aspect of cellular physiology, including stem cell regulation during embryonic development and in adult organisms. The protein-deacetylase, SIRT1, has received much attention because of its roles in oxygen metabolism, cellular stress response, aging, and has been investigated in various species and cell types including embryonic stem cells. However, there is a dearth of information on SIRT1 in adult stem cells, which have a pivotal role in adult aging processes. Here, we discuss the potential relationships between SIRT1 and the surface receptor protein, Notch, with stem cell self-renewal, asymmetric cell division, signaling, and stem cell aging.     

Characterization of histone inheritance patterns in the Drosophila female germline

Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that during a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combine histone labeling with DNA Oligopaints to distinguish old versus new histones and visualize their inheritance patterns at a single‐gene resolution in asymmetrically dividing cells in vivo. This strategy can be applied to other biological systems involving cell fate change during development or tissue homeostasis in multicellular organisms.     

Mechanisms of asymmetric cell division: flies and worms pave the way

Asymmetric cell division is fundamental for generating diversity in multicellular organisms. The mechanisms that govern asymmetric cell division are increasingly well understood, owing notably to studies that were conducted in Drosophila melanogaster and Caenorhabditis elegans. Lessons learned from these two model organisms also apply to cells that divide asymmetrically in other metazoans, such as self-renewing stem cells in mammals.     

Polarity in Stem Cell Division: Asymmetric Stem Cell Division in Tissue Homeostasis

Many adult stem cells divide asymmetrically to balance self-renewal and differentiation, thereby maintaining tissue homeostasis. Asymmetric stem cell divisions depend on asymmetric cell architecture (i.e., cell polarity) within the cell and/or the cellular environment. In particular, as residents of the tissues they sustain, stem cells are inevitably placed in the context of the tissue architecture. Indeed, many stem cells are polarized within their microenvironment, or the stem cell niche, and their asymmetric division relies on their relationship with the microenvironment. Here, we review asymmetric stem cell divisions in the context of the stem cell niche with a focus on Drosophila germ line stem cells, where the nature of niche-dependent asymmetric stem cell division is well characterized.Asymmetric cell division allows stem cells to self-renew and produce another cell that undergoes differentiation, thus providing a simple method for tissue homeostasis. Stem cell self-renewal refers to the daughter(s) of stem cell division maintaining all stem cell characteristics, including proliferation capacity, maintenance of the undifferentiated state, and the capability to produce daughter cells that undergo differentiation. A failure to maintain the correct stem cell number has been speculated to lead to tumorigenesis/tissue hyperplasia via stem cell hyperproliferation or tissue degeneration/aging via a reduction in stem cell number or activity (Morrison and Kimble 2006; Rando 2006). This necessity changes during development. The stem cell pool requires expansion earlier in development, whereas maintenance is needed later to sustain tissue homeostasis.There are two major mechanisms to sustain a fixed number of adult stem cells: stem cell niche and asymmetric stem cell division, which are not mutually exclusive. Stem cell niche is a microenvironment in which stem cells reside, and provides essential signals required for stem cell identity (Fig. 1A). Physical limitation of niche “space” can therefore define stem cell number within a tissue. Within such a niche, many stem cells divide asymmetrically, giving rise to one stem cell and one differentiating cell, by placing one daughter inside and another outside of the niche, respectively (Fig. 1A). Nevertheless, some stem cells divide asymmetrically, apparently without the niche. For example, in Drosophila neuroblasts, cell-intrinsic fate determinants are polarized within a dividing cell, and subsequent partitioning of such fate determinants into daughter cells in an asymmetric manner results in asymmetric stem cell division (Fig. 1B) (see Fig. 3A and Prehoda 2009).Open in a separate windowFigure 1.Mechanisms of asymmetric stem cell division. (A) Asymmetric stem cell division by extrinsic fate determinants (i.e., the stem cell niche). The two daughters of stem cell division will be placed in distinct cellular environments either inside or outside the stem cell niche, leading to asymmetric fate choice. (B) Asymmetric stem cell division by intrinsic fate determinants. Fate determinants are polarized in the dividing stem cells, which are subsequently partitioned into two daughter cells unequally, thus making the division asymmetrical. Self-renewing (red line) and/or differentiation promoting (green line) factors may be involved.In this review, we focus primarily on asymmetric stem cell divisions in the Drosophila germ line as the most intensively studied examples of niche-dependent asymmetric stem cell division. We also discuss some examples of stem cell division outside Drosophila, where stem cells are known to divide asymmetrically or in a niche-dependent manner.     

Asymmetric cell division in the morphogenesis of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> macrochaetae

Asymmetric cell division (ACD) is the basic process which creates diversity in the cells of multi-cellular organisms. As a result of asymmetric cell division, daughter cells acquire the ability to differentiate and specialize in a given direction, which is different from that of their parent cells and from each other. This type of division is observed in a wide range of living organisms from bacteria to vertebrates. It has been shown that the molecular-genetic control mechanism of ACD is evolutionally conservative. The proteins involved in the process of ACD in different kinds of animals have a high degree of homology. Sensory organs—bristles (macrochaetae)—of Drosophila are widely used as a model system for studying the genetic control mechanisms of asymmetric division. Bristles located in an orderly manner on the head and body of the fly play the role of mechanoreceptors. Each of them consists of four specialized cells—offspring of the only sensory organ precursor cell (SOP), which differentiates from the wing imaginal disc at the larval stage of the late third age. The basic differentiation and further specialization of the daughter cells of SOP is an asymmetric division process.     

Restricting self-renewal signals within the stem cell niche: multiple levels of control

Germline stem cells (GSCs) were the first stem cells demonstrated to be regulated by the microenvironment or niche in the Drosophila ovary a decade ago. In the Drosophila ovary, as a stem cell divides, one daughter remaining in the niche continues to self-renew, and the other daughter positioned outside the niche undergoes differentiation. The niche produces bone morphogenetic proteins (BMPs) that only act within one cell diameter to ensure that at every division only one of two GSC daughters self-renews and thus maintains a stable GSC pool. Within the past decade, great progress has been made toward understanding how functions of BMP niche signals are restricted to GSCs. In this review, we have discussed multiple levels of control underlying the restriction of BMP signals within the niche. Because the niche mechanism has been shown to regulate stem cells in various organisms including mammals, the knowledge gained from the Drosophila GSC niche should help gain a better understanding of how niche signals are controlled in other stem cell systems.     

Asymmetric cell division in the morphogenesis of Drosophila melanogaster macrochaetae

Asymmetric cell division (ACD) is the basic process which creates diversity in the cells of multicellular organisms. As a result of asymmetric cell division, daughter cells acquire the ability to differentiate and specialize in a given direction, which is different from that of their parent cells and from each other. This type of division is observed in a wide range of living organisms from bacteria to vertebrates. It has been shown that the molecular-genetic control mechanism of ACD is evolutionally conservative. The proteins involved in the process of ACD in different kinds of animals have a high degree of homology. Sensory organs--setae (macrochaetae)--of Drosophila are widely used as a model system for studying the genetic control mechanisms of asymmetric division. Setae located in an orderly manner on the head and body of the fly play the role of mechanoreceptors. Each of them consists of four specialized cells--offspring of the only sensory organ precursor cell (SOPC), which differentiates from the imaginal wing disc at the larval stage of the late third age. The basic differentiation and further specialization of the daughter cells of SOPC is an asymmetric division process. In this summary, experimental data on genes and their products controlling asymmetric division of SOPC and daughter cells, and also the specialization of the latter, have been systemized. The basic mechanisms which determine the time cells enter into asymmetric mitosis and which provides the structural characteristics of the asymmetric division process--the polar distribution of protein determinants Numb and Neuralized--the orientation of the mitotic spindle in relation to these determinants, and the uneven segregation of the determinants into the daughter cells that determines the direction of their development have been discussed.     

Quantitative analysis of germline mitosis in adult C. elegans

Certain aspects of the distal gonad of C. elegans are comparable to niche/stem cell systems in other organisms. The distal tip cell (DTC) caps a blind-ended tube; only the distal germ cells maintain proliferation in response to signaling from the DTC via the GLP-1/Notch signaling pathway in the germ line. Fruitful comparison between this system and other stem cell systems is limited by a lack of basic information regarding germ cell division behavior in C. elegans. Here, we explore the spatial pattern of cell division frequency in the adult C. elegans germ line relative to distance from the distal tip. We mapped the positions of actively dividing germline nuclei in over 600 fixed gonad preparations including the wild type and a gain-of-function ligand-responsive GLP-1 receptor mutant with an extended mitotic zone. One particularly surprising observation from these data is that the frequency of cell divisions is lower in distal-most cells-cells that directly contact the distal tip cell body-relative to cells further proximal, a difference that persists in the gain-of-function GLP-1 mutant. These results suggest that cell division frequency in the distal-most cells may be suppressed or otherwise controlled in a complex manner. Further, our data suggest that the presence of an active cell division influences the probability of observing simultaneous cell divisions in the same gonad arm, and that simultaneous divisions tend to cluster spatially. We speculate that this system behaves similarly to niche/stem cell/transit amplifying cell systems in other organisms.