Balancing self-renewal and differentiation by asymmetric division: insights from brain tumor suppressors in Drosophila neural stem cells

Balancing self-renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self-renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self-renewal control of Drosophila NBs. We summarize molecular mechanisms of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain-of-function or loss-of-function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division.     

Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells

Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.     

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。     

Stem cell niches in mammals

Stem cells safeguard tissue homeostasis and guarantee tissue repair throughout life. The decision between self-renewal and differentiation is influenced by a specialized microenvironment called stem cell niche. Physical and molecular interactions with niche cells and orientation of the cleavage plane during stem cell mitosis control the balance between symmetric and asymmetric division of stem cells. Here we highlight recent progress made on the anatomical and molecular characterization of mammalian stem cell niches, focusing particularly on bone marrow, tooth and hair follicle. The knowledge of the regulation of stem cells within their niches in health and disease will be instrumental to develop novel therapies that target stem cell niches to achieve tissue repair and re-establish tissue homeostasis.     

Mechanisms that mediate stem cell self-renewal and differentiation

Stem cells have two common properties: the capacity for self-renewal and the potential to differentiate into one or more specialized cell types. In general, stem cells can be divided into two broad categories: adult (somatic) stem cells and embryonic stem cells. Recent evidence suggested that tumors may contain "cancer stem cells" with indefinite potential for self-renewal. In this review, we will focus on the molecular mechanisms regulating embryonic stem cell self-renewal and differentiation, and discuss how these mechanisms may be relevant in cancer cells.     

Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation

Microenvironmental oxygen (O(2)) regulates stem cell activity, and a hypoxic niche with low oxygen levels has been reported in multiple stem cell types. Satellite cells are muscle-resident stem cells that maintain the homeostasis and mediate the regeneration of skeletal muscles. We demonstrate here that hypoxic culture conditions favor the quiescence of satellite cell-derived primary myoblasts by upregulating Pax7, a key regulator of satellite cell self-renewal, and downregulating MyoD and myogenin. During myoblast division, hypoxia promotes asymmetric self-renewal divisions and inhibits asymmetric differentiation divisions without affecting the overall rate of proliferation. Mechanistic studies reveal that hypoxia activates the Notch signaling pathway, which subsequently represses the expression of miR-1 and miR-206 through canonical Hes/Hey proteins, leading to increased levels of Pax7. More importantly, hypoxia conditioning enhances the efficiency of myoblast transplantation and the self-renewal of implanted cells. Given the robust effects of hypoxia on maintaining the quiescence and promoting the self-renewal of cultured myoblasts, we predict that oxygen levels in the satellite cell niche play a central role in precisely balancing quiescence versus activation, and self-renewal versus differentiation, in muscle stem cells in vivo.     

Proliferative control in Drosophila stem cells

The relationship between cell growth (cell mass increase over time) and cell division is poorly understood in animal stem cells. Recent studies in several Drosophila stem cell types have provided the tools to interrogate this relationship. In several cases (brat, mei-P26, pros, bam, lethal giant larvae, polo), mutations have been defined that trigger tumorous overproliferation of progenitor cells and reveal how unrestricted self-renewing capacity is controlled. Moreover, microRNAs have been discovered as essential regulators of stem cell division rate and identity, suggesting that stem cell self-renewal depends on protein translational control. Biosynthetic capacity has also been found to be limiting for stem cell division rates. Finally, asymmetric cell division can impose dominant differentiation signals in a stem cell's daughter, and this can inhibit the stem cell-specific proliferation signature and lock in cell cycle exit.     

骨髓间充质干细胞向肝细胞分化的相关细胞因子及信号通路的研究进展

骨髓干细胞包括造血干细胞（HSCs）和间充质干细胞（MSCs）,骨髓间充质干细胞（BMSCs）是一类具有自我更新、增殖和多向分化能力的细胞,具有不对称分裂和无限增殖的特点。在肝细胞生长因子（HGF）的作用下,BMSCs可以分化为肝细胞,参与诱导这一分化过程的相关信号通路包括NF-kB信号通路、Notch信号通路、MAPK信号通路、Wnt信号通路和STAT3信号通路。文章主要就BMSCs分化为肝细胞的相关信号通路进行了综述。     

机械力及力学信号转导影响干细胞命运的研究进展

干细胞作为一种未分化的祖细胞,目前已被广泛应用于开展组织损伤修复、再生以及干细胞特异谱系分化的研究.大量研究表明,干细胞所处的微环境对调控干细胞的生长和分化具有重要作用,多种溶液介质、细胞外基质和信号通路等参与了干细胞命运的调控.尽管已有大量研究证明,溶液介质(如激素和生长因子)在干细胞的生长和分化中发挥重要作用,但近年来越来越多的研究表明,机械力及力学信号转导同样在干细胞自我更新、分化、衰老和凋亡等细胞生理过程中起到重要的作用.本文将对机械应力响应的细胞基础、生物力学及力学信号调控干细胞自我更新和分化,以及生物力学调控干细胞命运可能的作用机制几个方面加以综述.     

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.     

Cancer stem cells: the theory and perspectives in cancer therapy

The cancer stem cell theory elucidates not only the issue of tumour initiation and development, tumour's ability to metastasise and reoccur, but also the ineffectiveness of conventional cancer therapy. This review examines stem cell properties, such as self-renewal, heterogeneity, and resistance to apoptosis. The 'niche' hypothesis is presented, and mechanisms of division, differentiation, self-renewal and signalling pathway regulation are explained. Epigenetic alterations and mutations of genes responsible for signal transmission may promote the formation of cancer stem cells. We also present the history of development of the cancer stem cell theory and discuss the experiments that led to the discovery and confirmation of the existence of cancer stem cells. Potential clinical applications are also considered, including therapeutic models aimed at selective elimination of cancer stem cells or induction of their proper differentiation.     

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.     

Neural stem cells: balancing self-renewal with differentiation

Stem cells are captivating because they have the potential to make multiple cell types yet maintain their undifferentiated state. Recent studies of Drosophila and mammalian neural stem cells have shed light on how stem cells regulate self-renewal versus differentiation and have revealed the proteins, processes and pathways that all converge to regulate neural progenitor self-renewal. If we can better understand how stem cells balance self-renewal versus differentiation, we will significantly advance our knowledge of embryogenesis, cancer biology and brain evolution, as well as the use of stem cells for therapeutic purposes.     

Dr. Haifan Lin. Interviewed by Han Lee and Rachel Rosenstein

Dr. Haifan Lin is professor of Cell Biology at Yale University, where he studies the mechanism of stem cell self-renewal in fruit flies, mice, and human cancer cells. Recently named director of the Yale Stem Cell Center, Dr. Lin has made seminal contributions to the stem cell field, most notably his demonstration of the stem cell niche theory using the fruit fly model, his discovery of the PIWI/AGO gene family that is essential for stem cell division in diverse organisms, and his recent finding of a group of small RNAs called PIWI-interacting, or piRNAs, which may play a crucial role in stem cell proliferation and germline development. Dr. Lin’s work on piRNAs was recognized by Science Magazine as a top scientific breakthrough of 2006. Recently, the Lin lab has begun exploring the role of these molecules in stem cell division and oncogenesis.     

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.     

小分子RNA决定果蝇生殖干细胞命运的分子机制研究

生殖干细胞是具有自我更新能力的一群生殖细胞,充当配子生成的源泉。果蝇生殖干细胞的特征在于通过不对称分裂产生两个子代细胞,一个通过自我更新维持干细胞特性,另一个则进行分化。生殖干细胞的命运受其周围的微环境——"干细胞niche"控制,而"niche"的功能又通过干细胞的外源和内源信号间的相互作用来完成。小分子RNA通过复杂的RNAi途径调控基因的表达。大量证据表明生殖干细胞的维持和分化需要小分子RNA参与,小分子RNA生成的紊乱会导致干细胞的"丢失"或"未分化"。该文综述了小分子RNA对果蝇生殖干细胞命运调控的研究进展,并讨论新发现的小分子RNA在生殖干细胞命运决定中的相关功能。