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      Functional lacrimal gland regeneration by transplantation of a bioengineered organ germ

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          Abstract

          The lacrimal gland has a multifaceted role in maintaining a homeostatic microenvironment for a healthy ocular surface via tear secretion. Dry-eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye diseases that cause corneal epithelial damage and results in significant loss of vision and a reduction in the quality of life. Here we demonstrate orthotopic transplantation of bioengineered lacrimal gland germs into adult mice with an extra-orbital lacrimal gland defect, a mouse model that mimics the corneal epithelial damage caused by lacrimal gland dysfunction. The bioengineered lacrimal gland germs and harderian gland germs both develop in vivo and achieve sufficient physiological functionality, including tear production in response to nervous stimulation and ocular surface protection. This study demonstrates the potential for bioengineered organ replacement to functionally restore the lacrimal gland.

          Abstract

          Lacrimal glands maintain a healthy corneal epithelium but are dysfunctional for example in dry-eye disease. Here, the authors transplant bioengineered lacrimal and harderian gland germs into mice, where they connect to the host duct and nervous system and restore lacrimal gland function.

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          Most cited references52

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          Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases.

          The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions.
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            The development of a bioengineered organ germ method.

            To bioengineer ectodermal organs such as teeth and whisker follicles, we developed a three-dimensional organ-germ culture method. The bioengineered tooth germ generated a structurally correct tooth, after both in vitro organ culture as well as transplantation under a tooth cavity in vivo, showing penetration of blood vessels and nerve fibers. Our method provides a substantial advance in the development of bioengineered organ replacement strategies and regenerative therapies.
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              Fully functional bioengineered tooth replacement as an organ replacement therapy.

              Current approaches to the development of regenerative therapies have been influenced by our understanding of embryonic development, stem cell biology, and tissue engineering technology. The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies. The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues. This study represents a substantial advance and emphasizes the potential for bioengineered organ replacement in future regenerative therapies.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                01 October 2013
                : 4
                : 2497
                Affiliations
                [1 ]Department of Ophthalmology, School of Medicine, Keio University , Shinjuku-ku, Tokyo 160 8582, Japan
                [2 ]Research Institute for Science and Technology, Tokyo University of Science , Noda, Chiba 278 8510, Japan
                [3 ]Division of Research and Development, Organ Technologies Inc. , Chiyoda-ku, Tokyo 101 0048, Japan
                [4 ]Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science , Noda, Chiba 278 8510, Japan
                [5 ]Institute for Advanced Biosciences, Keio University , Tsuruoka, Yamagata 997 0035, Japan
                Author notes
                Article
                ncomms3497
                10.1038/ncomms3497
                3806342
                24084941
                7f05f723-6e77-417e-8564-343e2da948d4
                Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. To view a copy of this licence visit http://creativecommons.org/licenses/by/3.0/.

                History
                : 01 February 2013
                : 23 August 2013
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