Derivation of rigorous conditions for high cell-type diversity by algebraic approach

The development of a multicellular organism is a dynamic process. Starting with one or a few cells, the organism develops into different types of cells with distinct functions. We have constructed a simple model by considering the cell number increase and the cell-type order conservation, and have assessed conditions for cell-type diversity. This model is based on a stochastic Lindenmayer system with cell-to-cell interactions for three types of cells. In the present model, we have successfully derived complex but rigorous algebraic relations between the proliferation and transition rates for cell-type diversity by using a symbolic method: quantifier elimination (QE). Surprisingly, three modes for the proliferation and transition rates have emerged for large ratios of the initial cells to the developed cells. The three modes have revealed that the equality between the development rates for the highest cell-type diversity is reduced during the development process of multicellular organisms. Furthermore, we have found that the highest cell-type diversity originates from order conservation.     

Regulation of cell-fate determination in Dictyostelium

A key step in the development of all multicellular organisms is the differentiation of specialized cell types. The eukaryotic microorganism Dictyostelium discoideum provides a unique experimental system for studying cell-type determination and spatial patterning in a developing multicellular organism. Unlike metazoans, which become multicellular by undergoing many rounds of cell division after fertilization of an egg, the social amoeba Dictyostelium achieves multicellularity by the aggregation of approximately 10(5) cells in response to nutrient depletion. Following aggregation, cell-type differentiation and morphogenesis result in a multicellular organism with only a few cell types that exhibit a defined patterning along the anterior-posterior axis of the organism. Analysis of the mechanisms that control these processes is facilitated by the relative simplicity of Dictyostelium development and the availability of molecular, genetic, and cell biological tools. Interestingly, analysis has shown that many molecules that play integral roles in the development of higher eukaryotes, such as PKA, STATs, and GSK-3, are also essential for cell-type differentiation and patterning in Dictyostelium. The role of these and other signaling pathways in the induction, maintenance, and patterning of cell types during Dictyostelium development is discussed.     

On the origin of differentiation

Following the origin of multicellularity in many groups of primitive organisms there evolved more than one cell type. It has been assumed that this early differentiation is related to size — the larger the organism the more cell types. Here two very different kinds of organisms are considered: the volvocine algae that become multicellular by growth, and the cellular slime moulds that become multicellular by aggregation. In both cases there are species that have only one cell type and others that have two. It has been possible to show that there is a perfect correlation with size: the forms with two cell types are significantly larger than those with one. Also in both groups there are forms of intermediate size that will vary from one to two cell types depending on the size of the individuals, suggesting a form of quorum sensing. These observations reinforce the view that size plays a critical role in influencing the degree of differentiation.     

Regulative differentiation as bifurcation of interacting cell population

In multicellular organisms, several cell states coexist. For determining each cell type, cell-cell interactions are often essential, in addition to intracellular gene expression dynamics. Based on dynamical systems theory, we propose a mechanism for cell differentiation with regulation of populations of each cell type by taking simple cell models with gene expression dynamics. By incorporating several interaction kinetics, we found that the cell models with a single intracellular positive-feedback loop exhibit a cell fate switching, with a change in the total number of cells. The number of a given cell type or the population ratio of each cell type is preserved against the change in the total number of cells, depending on the form of cell-cell interaction. The differentiation is a result of bifurcation of cell states via the intercellular interactions, while the population regulation is explained by self-consistent determination of the bifurcation parameter through cell-cell interactions. The relevance of this mechanism to development and differentiation in several multicellular systems is discussed.     

Differences in cell division rates drive the evolution of terminal differentiation in microbes

Multicellular differentiated organisms are composed of cells that begin by developing from a single pluripotent germ cell. In many organisms, a proportion of cells differentiate into specialized somatic cells. Whether these cells lose their pluripotency or are able to reverse their differentiated state has important consequences. Reversibly differentiated cells can potentially regenerate parts of an organism and allow reproduction through fragmentation. In many organisms, however, somatic differentiation is terminal, thereby restricting the developmental paths to reproduction. The reason why terminal differentiation is a common developmental strategy remains unexplored. To understand the conditions that affect the evolution of terminal versus reversible differentiation, we developed a computational model inspired by differentiating cyanobacteria. We simulated the evolution of a population of two cell types -nitrogen fixing or photosynthetic- that exchange resources. The traits that control differentiation rates between cell types are allowed to evolve in the model. Although the topology of cell interactions and differentiation costs play a role in the evolution of terminal and reversible differentiation, the most important factor is the difference in division rates between cell types. Faster dividing cells always evolve to become the germ line. Our results explain why most multicellular differentiated cyanobacteria have terminally differentiated cells, while some have reversibly differentiated cells. We further observed that symbioses involving two cooperating lineages can evolve under conditions where aggregate size, connectivity, and differentiation costs are high. This may explain why plants engage in symbiotic interactions with diazotrophic bacteria.     

Cells in the system of multicelular organism from positions of non-linear dynamics

The organism physiological systems forming a hierarchic network with mutual dependence and subordination can be considered as systems with non-linear dynamics including positive and negative feedbacks. In the course of evolution there occurred selection of robust, flexible, modular systems capable for adaptive self-organization by non-linear interaction of components, which leads to formation of the ordered in space and time robust and plastic organization of the whole. Cells of multicellular organisms are capable for coordinated “social” behavior with formation of ordered cell assemblies, which provides a possibility of morphological and functional variability correlating with manifestations of the large spectrum of adaptive reactions. The multicellular organism is the multilevel system with hierarchy of numerous subsystems capable for adaptive self-organization; disturbance of their homeostasis can lead to pathological changes. The healthy organism regulates homeostasis, self-renewal, differentiation, and apoptosis of cells serving its parts and construction blocks by preserving its integrity and controlling behavior of cells. The systemic approach taking into account biological regularities of the appearance and development of functions in evolution of multicellular organisms opens new possibilities for diagnostics and treatment of many diseases.     

Pathways regulating apoptosis during patterning and development

The patterning and development of multicellular organisms require a precisely controlled balance between cell proliferation, differentiation and death. The regulation of apoptosis is an important aspect to achieve this balance, by eliminating unnecessary or mis-specified cells which, otherwise, may have harmful effects on the whole organism. Apoptosis is also important for the morphogenetic processes that occur during development and that lead to the sculpting of organs and other body structures. Here, we review recent progress in understanding how apoptosis is regulated during development, focusing on studies using Drosophila or Caenorhabditis elegans as model organisms.     

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。     

Organizational requirements for multicellular autonomy: insights from a comparative case study

In this paper we explore the organizational conditions underlying the emergence of organisms at the multicellular level. More specifically, we shall propose a general theoretical scheme according to which a multicellular organism is an ensemble of cells that effectively regulates its own development through collective (meta-cellular) mechanisms of control of cell differentiation and cell division processes. This theoretical result derives from the detailed study of the ontogenetic development of three multicellular systems (Nostoc punctiforme, Volvox carteri and Strongylocentrotus purpuratus) and, in particular, of their corresponding cell-to-cell signaling networks. The case study supports our claim that a specific type of functional integration among the cells of a multicellular ensemble (namely, a regulatory control system consisting in several inter-cellular mechanisms that modulate epigenesis and whose operation gets decoupled from the intra-cellular metabolic machinery), is required for it to qualify as a proper organism. Finally, we argue why a multicellular system exhibiting this type of functionally differentiated and integrated developmental organization becomes a self-determining collective entity and, therefore, should be considered as a second-order autonomous system.     

植物根尖干细胞的表观遗传调控

干细胞是一类具有特化为不同细胞类型能力的多能性细胞,他为多细胞生物的器官发生、损伤修复和再生源源不断提供新细胞。干细胞的特化和维持需要复杂的基因调控网络来有序调控。此外,表观遗传调控在包括干细胞命运决定在内的许多生物学过程中发挥极其重要的作用。本文归纳了近年来对植物,主要是模式植物拟南芥（Arabidopsis thaliana（L.）Heynh.）根尖干细胞表观遗传调控方面的研究进展,重点论述了表观调控因子与控制干细胞的关键转录因子之间如何互作、调控植物根尖干细胞的自我更新和分化,并对今后研究的突破方向进行了展望。     

Animal cell differentiation patterns suppress somatic evolution

Cell differentiation in multicellular organisms has the obvious function during development of creating new cell types. However, in long-lived organisms with extensive cell turnover, cell differentiation often continues after new cell types are no longer needed or produced. Here, we address the question of why this is true. It is believed that multicellular organisms could not have arisen or been evolutionarily stable without possessing mechanisms to suppress somatic selection among cells within organisms, which would otherwise disrupt organismal integrity. Here, we propose that one such mechanism is a specific pattern of ongoing cell differentiation commonly found in metazoans with cell turnover, which we call “serial differentiation.” This pattern involves a sequence of differentiation stages, starting with self-renewing somatic stem cells and proceeding through several (non–self-renewing) transient amplifying cell stages before ending with terminally differentiated cells. To test the hypothesis that serial differentiation can suppress somatic evolution, we used an agent-based computer simulation of cell population dynamics and evolution within tissues. The results indicate that, relative to other, simpler patterns, tissues organized into serial differentiation experience lower rates of detrimental cell-level evolution. Self-renewing cell populations are susceptible to somatic evolution, while those that are not self-renewing are not. We find that a mutation disrupting differentiation can create a new self-renewing cell population that is vulnerable to somatic evolution. These results are relevant not only to understanding the evolutionary origins of multicellularity, but also the causes of pathologies such as cancer and senescence in extant metazoans, including humans.     

TGF-β family signaling in stem cells

Background

The diversity of cell types and tissue types that originate throughout development derives from the differentiation potential of embryonic stem cells and somatic stem cells. While the former are pluripotent, and thus can give rise to a full differentiation spectrum, the latter have limited differentiation potential but drive tissue remodeling. Additionally cancer tissues also have a small population of self-renewing cells with stem cell properties. These cancer stem cells may arise through dedifferentiation from non-stem cells in cancer tissues, illustrating their plasticity, and may greatly contribute to the resistance of cancers to chemotherapies.

Scope of review

The capacity of the different types of stem cells for self-renewal, the establishment and maintenance of their differentiation potential, and the selection of differentiation programs are greatly defined by the interplay of signaling molecules provided by both the stem cells themselves, and their microenvironment, the niche. Here we discuss common and divergent roles of TGF-β family signaling in the regulation of embryonic, reprogrammed pluripotent, somatic, and cancer stem cells.

Major conclusions

Increasing evidence highlights the similarities between responses of normal and cancer stem cells to signaling molecules, provided or activated by their microenvironment. While TGF-β family signaling regulates stemness of normal and cancer stem cells, its effects are diverse and depend on the cell types and physiological state of the cells.

General significance

Further mechanistic studies will provide a better understanding of the roles of TGF-β family signaling in the regulation of stem cells. These basic studies may lead to the development of a new therapeutic or prognostic strategies for the treatment of cancers. This article is part of a Special Issue entitled Biochemistry of Stem Cells.     

Mechanisms regulating the origins of the vertebrate vascular system

In order to sustain growth, differentiation, and organogenesis, vertebrate embryos must form a functional vascular system early in embryonic development. Intrinsic interest in this process as well as the promise of potential clinical applications has led to significant progress in understanding the mechanisms governing the formation of the vascular system, however the earliest stages of vascular development--the emergence of committed endothelial precursors from the mesoderm--remain unclear. A review of the current literature reveals an unexpected diversity and heterogeneity with respect to where vascular endothelial cells originate in the embryo, when they become committed and the mechanisms governing how endothelial cells acquire their identity. Spatially, a widespread region of the early mesoderm possesses the ability to give rise to vascular endothelial cells; temporally the process is not limited to a small window during embryogenesis, but rather, may continue throughout the lifespan of the organism. On the molecular level, recent findings point to several determinative pathways that regulate, modulate, and extend the scope of the Flk1/VEGF signaling system. An expanding array of novel gene products implicated in endothelial cell type determination appear to act synergistically, with different combinations of factors leading to diverse cellular responses, varying patterns of differentiation, and considerable heterogeneity of endothelial cell types during embryogenesis.     

Application of a systems approach to study developmental gene regulation

All cells in a multicellular organism contain the same genome, yet different cell types express different sets of genes. Recent advances in high throughput genomic technologies have opened up new opportunities to understand the gene regulatory network in diverse cell types in a genome-wide manner. Here, I discuss recent advances in experimental and computational approaches for the study of gene regulation in embryonic development from a systems perspective. This review is written for computational biologists who have an interest in studying developmental gene regulation through integrative analysis of gene expression, chromatin landscape, and signaling pathways. I highlight the utility of publicly available data and tools, as well as some common analysis approaches.     

Robust development as a consequence of generated positional information

The origin and robustness of morphogenesis are studied by dynamical system modeling of a cell society, in which cells possessing internal chemical reaction dynamics interact with each other through their mutual interaction with diffusive chemicals in a two-dimensional medium. It is found that stem-type cells differentiate into various cell types (where a cell 'type' is defined by a type of intra-cellular dynamics) due to a dynamic instability caused by cell-cell interactions in a manner described by the isologous diversification theory. The differentiations are spatially regulated by the concentration of chemicals in the medium, while the chemical concentrations are locally influenced by the intra-cell dynamics. Through this reciprocal relationship, chemical concentrations come to exhibit spatial variation as differentiated cell types begin to emerge, and as a result the regulation exercised by the chemical concentrations become spatially inhomogeneous. This reinforces the process of differentiation, through which spatial patterns of differentiated cells appear. Within this reciprocal relationship, the concentration gradients are read and interpreted by the cell as positional information. A spatial order of cells realized in this process represents a stable state of the system governed by this reciprocal relationship, and that the developmental process through which this state is realized is robust with respect to perturbations. The dependence of the morphogenesis on history and the community effect in cell differentiation are also discussed.     

cki-1 links cell division and cell fate acquisition in the C. elegans somatic gonad

The formation of a complex multicellular organism requires the precise specification of many diverse cell types at the correct time and position throughout development. This may be achieved by coordinating cell fate specification processes with progression through the cell cycle. Here, we show that the extra distal tip cells (DTCs) associated with the loss of cki-1, a Caenorhabditis elegans homologue of the cyclin-dependent kinase inhibitor p27, do not arise from duplications of pre-existing DTCs, but that they are formed from another cell type within the somatic gonad. Results from our laser microsurgery experiments suggest that the extra DTCs are caused by aberrant somatic gonadal precursor cell divisions in the absence of cki-1, resulting in abnormal daughter cell fates. cki-1(RNAi) animals also possess extra anchor cells and ectopic gonad arms with variable sheath cell numbers and positioning. In addition, cki-1(RNAi) animals display an endomitotic oocyte (Emo) phenotype. Our results uncover a novel role of this CKI in cell fate acquisition, either by directly influencing specification, or through a more conventional role in appropriately linking cell cycle phase with this process.