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The self-made eye: Formation of optic cup from ES cells

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Developmental processes are increasingly well-characterized at the molecular and cell biological levels, but how more complex tissues and organs involving the coordinated action of multiple cell types in three dimensions is achieved remains something of a black box. One question of particular interest and importance is whether signaling interactions between neighboring tissues are essential to guiding organogenesis, or whether these can arise autonomously from developmental routines inherent to a given primordial tissue. Finding answers to these questions will be critical both to a better understanding of embryonic phenomena and to the ability to control the differentiation of cell populations into desired configurations. A breakthrough new report by Mototsugu Eiraku, deputy leader of the

Four-dimensional Tissue Analysis Unit and colleagues in the Laboratory for Neurogenesis and Organogenesis (Group Director, Yoshiki Sasai), as well as the RIKEN VCAD Program, and Kyoto and Osaka Universities, describes how mouse embryonic stem cells (ESCs) are able to differentiate and assemble into an optic cup, capable of giving rise to a tissue exhibiting the stratified structure characteristic of the retina in vivo. Published in Nature, the study used a cutting-edge three-dimensional tissue culture system not only to demonstrate this self organizing capacity of pluripotent stem cells, but the underlying cell dynamics as well. The mechanistic basis for the formation of the optic cup, with its complex two-walled structure, has been a longstanding question in embryology. The retina, with its origins in the lateral midbrain, is part of the central nervous system. Its development begins with the formation of the optic vesicle, a pocket of epithelium that deepens and pinches to form the optic cup, which develops a double layer of cells, with pigment epithelium on the outer, and neural retina on the inner wall. It has generally been thought that this transformation is triggered by chemical and physical influences from other tissues, such as lens or

cornea, but some, including the father of experimental embryology, Hans Spemann, have suggested that perhaps external induction or force is not necessary. To resolve this question, Eiraku et al. built on a series of techniques and findings emerging from the use of the SFEBq (serum-free culture of embryoid body–like aggregates) ES cell culture system developed by the Sasai lab, which had previously been used to differentiate these pluripotent stem cells into a wide range of neuronal cell types, including, recently, structurally organized cerebral cortical neurons. By adding extracellular matrix proteins to the SFEBq medium, the group was able to epithelially-organized retinal precursors at high efficiencies by day 7 of culture. One day later, optic vesicle-like structure began to form, followed by bi-layered optic cup-like structures by day 10. The pigmented and neuronal character of the outer and inner layers of cells in these spontaneously formed tissues were confirmed by gene expression, indicating that optic cup development had been recapitulated in vitro, and importantly, in the absence of any external signaling sources, such as lens, demonstrating the capacity for self-organization. They next used multi-photon microscopy to explore the mechanisms behind this

process of self-assembly in 3D. They found that after the ES cell-derived retinal precursors differentiated into pigmented epithelial and neuronal layers, the tissue underwent a four step morphological rearrangement on its way to assuming the optic cup structure. When they examined cytoskeletal behaviors in this process, they noted that myosin activity dropped in the region of the epithelium that bend inward to form the cup, giving the flexibility needed to form a pocket driven by expansion of the epithelium through cell division.  Computer simulation of the mechanics behind this revealed that three principal forces can explain the optic cup-forming event. First, the a region of the epithelium must lose rigidity, allowing it to buckle inward, after which cells at the hinge points (defined by the border between presumptive pigment epithelium and neuronal regions) must undergo apical constriction, giving them a wedge-like shape. Once these conditions are met, expansion of the tissue surface by cell division results further involution of the cup, all of which are very much in line with the experimental findings. As a final test of the in vitro structure’s ability to mirror its embryonic counterpart, Eiraku excised the neuronal layer from the ES

cell-derived optic cup and allowed it to develop in 3D cell culture under conditions optimized for spurring neuronal maturation. He found that the retinal neurons underwent active mitosis and ultimately organized into a six-layer stratified and synapse-forming neuronal structure closely resembling that of the post-natal retina. “What we’ve been able to do in this study is resolve a nearly century-old problem in embryology, by showing that retinal precursors have the inherent ability to give rise to the complex structure of the optic cup,” says Sasai. “It’s exciting to think that we are now well on the way to becoming able to generate not only differentiated cell types, but organized tissues from ES and iPS cells, which may open new avenues toward applications in regenerative medicine.” Potential applications include regenerative medicine approaches to the treatment of retinal degenerative disorders, such as retinitis pigmentosa. – Human Stem Cell Technology Unit (Yoshiki Sasai); Research Areas;Despite their great promise and fundamental interest, stem cells ? both embryonic and somatic ? can be challenging to study and manipulate in vitro. The Division of Human Stem Cell Technology (DHSCT) was established to provide a full spectrum of support services to labs within the CDB and throughout Japan with an interest in using human embryonic stem cells (hESCs) and their derivatives in their research. The DHSCT provides

technological expertise, training and support in hESC culture, maintenance, distribution and management, meeting the needs of both experienced and first-time users in the life sciences research community. Working with labs in academia and industry, the DHSCRT seeks to contribute to achieving the goals of translational research, in line with the CDB mission to establish a solid scientific foundation for regenerative medicine. – Organogenesis and Neurogenesis;  The complexity of the fully formed brain defies description, yet this organ arises from a nondescript clump of cells in the embryo. The specification of the dorsal-ventral (back-belly) axis is significant in neural development in that the central nervous system forms on the dorsal side of the body in all vertebrate orders. This process is dictated by the effects of a number of signaling factors that diffuse from organizing centers and direct dorsal ectoderm to maintain a neural fate. These molecules, which include Noggin, Chordin, Follistatin and their homologs, participate in elaborate signaling networks in which factors collaborate and compete to initiate the embryonic nervous

system. Using the African clawed frog, Xenopus laevis , as a model in molecular embryological studies, our group is engaged in clarifying the structure and extent of the signaling networks involved in setting up the dorsal-ventral axis and determining neural fate in the ectoderm. These studies focus on molecules that operate at early stages in embryonic development to lay down a complex of permissive, instructive and inhibitory patterns that determines the growth and differentiation of the brain in its earliest stages of development. The group is now also actively developing effective methods of inducing neuralization in mammals, work which it is hoped will contribute to basic research by providing in vitro experimental systems for use in the analysis of mammalian neurogenesis. In addition, this approach has potential for applications in the treatment of neurodegenerative disorders, such as Parkinson disease. Using a system developed in our lab, we have succeeded in inducing mouse and primate embryonic stem (ES) cells to differentiate into a range of specialized neuronal types. The application of similar techniques to human ES cells represents a field of study that, although it remains at quite an early stage, shows immense clinical promise.  By studying very early neurogenesis, and the mechanisms of neuronal differentiation, our lab aims to understand the molecular basis underpinningthe formation of so intricate a system as the mammalian neural network, in the hopes that, by looking at the elegant simplicity of the embryonic brain, it may one day be possible to understand the cellular bases of the mind’s activity. Contact: Douglas Sipp.    RIKEN CDB, Office for Science Communications and International Affairs. News from: RIKEN Center for Developmental Biology

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