The Role of Symmetric Stem Cell Divisions in Tissue Homeostasis

Successful maintenance of cellular lineages critically depends on the fate decision dynamics of stem cells (SCs) upon division. There are three possible strategies with respect to SC fate decision symmetry: (a) asymmetric mode, when each and every SC division produces one SC and one non-SC progeny; (b) symmetric mode, when 50% of all divisions produce two SCs and another 50%—two non-SC progeny; (c) mixed mode, when both the asymmetric and two types of symmetric SC divisions co-exist and are partitioned so that long-term net balance of the lineage output stays constant. Theoretically, either of these strategies can achieve lineage homeostasis. However, it remains unclear which strategy(s) are more advantageous and under what specific circumstances, and what minimal control mechanisms are required to operate them. Here we used stochastic modeling to analyze and quantify the ability of different types of divisions to maintain long-term lineage homeostasis, in the context of different control networks. Using the example of a two-component lineage, consisting of SCs and one type of non-SC progeny, we show that its tight homeostatic control is not necessarily associated with purely asymmetric divisions. Through stochastic analysis and simulations we show that asymmetric divisions can either stabilize or destabilize the lineage system, depending on the underlying control network. We further apply our computational model to biological observations in the context of a two-component lineage of mouse epidermis, where autonomous lineage control has been proposed and notable regional differences, in terms of symmetric division ratio, have been noted—higher in thickened epidermis of the paw skin as compared to ear and tail skin. By using our model we propose a possible explanation for the regional differences in epidermal lineage control strategies. We demonstrate how symmetric divisions can work to stabilize paw epidermis lineage, which experiences high level of micro-injuries and a lack of hair follicles as a back-up source of SCs.     

Dynamic Interplay of Spectrosome and Centrosome Organelles in Asymmetric Stem Cell Divisions

Stem cells have remarkable self-renewal ability and differentiation potency, which are critical for tissue repair and tissue homeostasis. Recently it has been found, in many systems (e.g. gut, neurons, and hematopoietic stem cells), that the self-renewal and differentiation balance is maintained when the stem cells divide asymmetrically. Drosophila male germline stem cells (GSCs), one of the best characterized model systems with well-defined stem cell niches, were reported to divide asymmetrically, where centrosome plays an important role. Utilizing time-lapse live cell imaging, customized tracking, and image processing programs, we found that most acentrosomal GSCs have the spectrosomes reposition from the basal end (wild type) to the apical end close to hub-GSC interface (acentrosomal GSCs). In addition, these apically positioned spectrosomes were mostly stationary while the basally positioned spectrosomes were mobile. For acentrosomal GSCs, their mitotic spindles were still highly oriented and divided asymmetrically with longer mitosis duration, resulting in asymmetric divisions. Moreover, when the spectrosome was knocked out, the centrosomes velocity decreased and centrosomes located closer to hub-GSC interface. We propose that in male GSCs, the spectrosome recruited to the apical end plays a complimentary role in ensuring proper spindle orientation when centrosome function is compromised.     

Condensins I and II are essential for construction of bivalent chromosomes in mouse oocytes

In many eukaryotes, condensins I and II associate with chromosomes in an ordered fashion during mitosis and play nonoverlapping functions in their assembly and segregation. Here we report for the first time the spatiotemporal dynamics and functions of the two condensin complexes during meiotic divisions in mouse oocytes. At the germinal vesicle stage (prophase I), condensin I is present in the cytoplasm, whereas condensin II is localized within the nucleus. After germinal vesicle breakdown, condensin II starts to associate with chromosomes and becomes concentrated onto chromatid axes of bivalent chromosomes by metaphase I. REC8 "glues" chromosome arms along their lengths. In striking contrast to condensin II, condensin I localizes primarily around centromeric regions at metaphase I and starts to associate stably with chromosome arms only after anaphase I. Antibody injection experiments show that condensin functions are required for many aspects of meiotic chromosome dynamics, including chromosome individualization, resolution, and segregation. We propose that the two condensin complexes play distinctive roles in constructing bivalent chromosomes: condensin II might play a primary role in resolving sister chromatid axes, whereas condensin I might contribute to monopolar attachment of sister kinetochores, possibly by assembling a unique centromeric structure underneath.     

Asymmetric Cell Divisions of Human Hematopoietic Stem and Progenitor Cells Meet Endosomes

Hematopoietic stem cells (HSC) are undifferentiated cells, which self-renew over a long period of time and give rise to committed hematopoietic progenitor cells (HPC) containing the capability to replenish the whole blood system. Since both uncontrolled expansion as well as loss of HSC would be fatal, the decision of self-renewal versus differentiation needs to be tightly controlled. There is good evidence that both HSC niches as well as asymmetric cell divisions are involved in controlling whether HSC self-renew or become committed to differentiate. In this context, we recently identified four proteins which frequently segregate asymmetrically in dividing HSC/HPC. Remarkably, three of these proteins, the tetraspanins CD53 and CD63, and the transferrin receptor are endosome-associated proteins. Here, we highlight these observations in conjunction with recent findings in model organisms which show that components of the endosomal machinery are involved in cell-fate specification processes.     

Asymmetric Segregation of the Double-Stranded RNA Binding Protein Staufen2 during Mammalian Neural Stem Cell Divisions Promotes Lineage Progression

Asymmetric cell divisions are a fundamental feature of neural development, and misregulation can lead to brain abnormalities or tumor formation. During an asymmetric cell division, molecular determinants are segregated preferentially into one daughter cell to specify its fate. An important goal is to identify the asymmetric determinants in neural progenitor cells, which could be tumor suppressors or inducers of specific neural fates. Here, we show that the double-stranded RNA-binding protein Stau2 is distributed asymmetrically during progenitor divisions in the developing mouse cortex, preferentially segregating into the Tbr2(+) neuroblast daughter, taking with it a subset of RNAs. Knockdown of Stau2 stimulates differentiation and overexpression produces periventricular neuronal masses, demonstrating its functional importance for normal cortical development. We immunoprecipitated Stau2 to examine its cargo mRNAs, and found enrichment for known asymmetric and basal cell determinants, such as Trim32, and identified candidates, including a subset involved in primary cilium function.     

Spatial and temporal regulation of Condensins I and II in mitotic chromosome assembly in human cells

Two different condensin complexes make distinct contributions to metaphase chromosome architecture in vertebrate cells. We show here that the spatial and temporal distributions of condensins I and II are differentially regulated during the cell cycle in HeLa cells. Condensin II is predominantly nuclear during interphase and contributes to early stages of chromosome assembly in prophase. In contrast, condensin I is sequestered in the cytoplasm from interphase through prophase and gains access to chromosomes only after the nuclear envelope breaks down in prometaphase. The two complexes alternate along the axis of metaphase chromatids, but they are arranged into a unique geometry at the centromere/kinetochore region, with condensin II enriched near the inner kinetochore plate. This region-specific distribution of condensins I and II is severely disrupted upon depletion of Aurora B, although their association with the chromosome arm is not. Depletion of condensin subunits causes defects in kinetochore structure and function, leading to aberrant chromosome alignment and segregation. Our results suggest that the two condensin complexes act sequentially to initiate the assembly of mitotic chromosomes and that their specialized distribution at the centromere/kinetochore region may play a crucial role in placing sister kinetochores into the back-to-back orientation.     

神经祖细胞不对称分裂中纺锤体取向与细胞皮层极性的偶联机制

神经祖细胞的不对称分裂是神经发生的必要环节.近年来关于不对称分裂的研究,为果蝇及哺乳动物中枢神经系统发育期间神经祖细胞的分化机制提供了新的理解.在这一分裂模式中,纺锤体作为细胞结构的支架,受到细胞皮层极性信号的引导而改变取向,保证底部细胞命运决定子(cell fate determinants)的不对称分配.G蛋白亚基、各种接头蛋白及微管相关蛋白组成极性蛋白复合体,在纺锤体取向改变中发挥了有序的调节作用.现在细胞和分子水平探讨不对称分裂纺锤体与细胞皮层极性偶联这一标志性事件.     

外遗调节与神经干细胞分化

神经发生与神经干细胞的分化调控机制是当今神经发育生物学的重要研究热点,在阐明干细胞的可塑性机制和临床治疗神经退行性疾病等方面具有广阔的应用前景。最近研究表明,外遗调节在神经干细胞的生长及分化方面表现出重要作用。这些外遗调节包括组蛋白的乙酰化/去乙酰化,DNA甲基化以及非编码RNAs对细胞命运决定的影响。     

Human Mesenchymal Stem Cells Signals Regulate Neural Stem Cell Fate

Neural stem cells (NSCs) differentiate into neurons, astrocytes and oligodendrocytes depending on their location within the central nervous system (CNS). The cellular and molecular cues mediating end-stage cell fate choices are not completely understood. The retention of multipotent NSCs in the adult CNS raises the possibility that selective recruitment of their progeny to specific lineages may facilitate repair in a spectrum of neuropathological conditions. Previous studies suggest that adult human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after a wide range of CNS insults, probably through their trophic influence. In the context of such trophic activity, here we demonstrate that hMSCs in culture provide humoral signals that selectively promote the genesis of neurons and oligodendrocytes from NSCs. Cell–cell contacts were less effective and the proportion of hMSCs that could be induced to express neural characteristics was very small. We propose that the selective promotion of neuronal and oligodendroglial fates in neural stem cell progeny is responsible for the ability of MSCs to enhance recovery after a wide range of CNS injuries. Special issue dedicated to Anthony Campagnoni.     

Uncoupling VEGFA Functions in Arteriogenesis and Hematopoietic Stem Cell Specification

1. Download : Download high-res image (104KB)
2. Download : Download full-size image

Highlights? VEGFA short isoform supports endothelial/arterial development of the dorsal aorta ? ETO2 maintains high levels of VEGFA medium and long isoforms in the somites ? VEGFA medium isoform instructs the blood program in blood stem cell precursors ? ETO2 specifies blood stem cells in a non-cell-autonomous manner     

PLZF与哺乳动物雄性生殖干细胞的发育分化

早幼粒细胞白血病锌指蛋白（promyelocytic leukemia zinc finger,PLZF）,也被称为ZBTB16(zinc finger and BTB domain containing 16,ZBTB16)或锌指蛋白145(zinc finger protein 145,ZFP145),是我国学者发现与人类疾病相关的蛋白质.人类PLZF的是由673个氨基酸残基组成的转录抑制因子,属于蛋白质超家族. 该超家族以N端的BTB/POZ（bric-à-brac, tramtrack, brad complex(BTB)/poxvirus zinc finger (POZ) domain）结构为特征. PLZF蛋白的BTB/POZ结构与个体发育、胚胎发生、染色体的重构等事件相关.近年发现,PLZF在哺乳动物雄性生殖干细胞（male germline stem cells,mGSCs）发育分化过程中也发挥重要作用.探讨PLZF的生物学功能和作用机制,将有助于理解其在mGSCs发育过程中的重要作用. 本文就PLZF在维持mGSCs自我更新和在发育分化调控中的作用给予综述.     

神经干细胞移植研究进展

神经干细胞是指一类具有自我更新能力和多向分化潜能的细胞,能分化成为神经元、星形胶质细胞、少突胶质细胞等众多神经细胞。成年哺乳动物内源性神经再生能力有限,无法弥补因神经疾病而导致的神经细胞缺失,因而,人们开始寻求外源性神经干细胞移植治疗中枢神经系统疾病的可能,在动物模型上开展了大量研究,并建立了多种移植方法。该文就神经干细胞的特性、来源、移植方式、在中枢神经系统疾病中的实验研究进展等作一综述。     

干细胞不对称分裂模式与肿瘤发生

干细胞发育中存在对称/不对称两种方式的交替分裂,精确调控维持正常发育。相关调控因素有外源性机制和内源性机制,发现于基本模式生物果蝇,主要包括干细胞周围微环境、细胞极性、纺锤体轴向和命运决定子不对称分布。调控机制的失常将导致干细胞分裂模式紊乱,可能造成肿瘤发生。简要综述了相关研究进展。     

神经干细胞/前体细胞分化的功能学鉴定研究进展

神经干细胞／前体细胞分化是神经生物学研究的热点．以往对神经干细胞／前体细胞分化水平的鉴定主要依赖于形态学指标,而随着膜片钳技术的应用,神经干细胞／前体细胞分化过程中膜电特性的改变、离子通道活动等功能学指标越来越受到重视．综述了利用膜片钳技术研究神经干细胞／前体细胞功能分化的最新进展,并对存在的问题做出思考和展望．     

Class I Myosins Have Overlapping and Specialized Functions in Left-Right Asymmetric Development in Drosophila

The class I myosin genes are conserved in diverse organisms, and their gene products are involved in actin dynamics, endocytosis, and signal transduction. Drosophila melanogaster has three class I myosin genes, Myosin 31DF (Myo31DF), Myosin 61F (Myo61F), and Myosin 95E (Myo95E). Myo31DF, Myo61F, and Myo95E belong to the Myosin ID, Myosin IC, and Myosin IB families, respectively. Previous loss-of-function analyses of Myo31DF and Myo61F revealed important roles in left–right (LR) asymmetric development and enterocyte maintenance, respectively. However, it was difficult to elucidate their roles in vivo, because of potential redundant activities. Here we generated class I myosin double and triple mutants to address this issue. We found that the triple mutant was viable and fertile, indicating that all three class I myosins were dispensable for survival. A loss-of-function analysis revealed further that Myo31DF and Myo61F, but not Myo95E, had redundant functions in promoting the dextral LR asymmetric development of the male genitalia. Myo61F overexpression is known to antagonize the dextral activity of Myo31DF in various Drosophila organs. Thus, the LR-reversing activity of overexpressed Myo61F may not reflect its physiological function. The endogenous activity of Myo61F in promoting dextral LR asymmetric development was observed in the male genitalia, but not the embryonic gut, another LR asymmetric organ. Thus, Myo61F and Myo31DF, but not Myo95E, play tissue-specific, redundant roles in LR asymmetric development. Our studies also revealed differential colocalization of the class I myosins with filamentous (F)-actin in the brush border of intestinal enterocytes.