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      Kidney Specific Protein-Positive Cells Derived from Embryonic Stem Cells Reproduce Tubular Structures In Vitro and Differentiate into Renal Tubular Cells

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          Abstract

          Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.

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          Most cited references28

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          Establishment in culture of pluripotential cells from mouse embryos.

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            Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors.

            Interaction between endothelial cells and mural cells (pericytes and vascular smooth muscle) is essential for vascular development and maintenance. Endothelial cells arise from Flk1-expressing (Flk1+) mesoderm cells, whereas mural cells are believed to derive from mesoderm, neural crest or epicardial cells and migrate to form the vessel wall. Difficulty in preparing pure populations of these lineages has hampered dissection of the mechanisms underlying vascular formation. Here we show that Flk1+ cells derived from embryonic stem cells can differentiate into both endothelial and mural cells and can reproduce the vascular organization process. Vascular endothelial growth factor promotes endothelial cell differentiation, whereas mural cells are induced by platelet-derived growth factor-BB. Vascular cells derived from Flk1+ cells can organize into vessel-like structures consisting of endothelial tubes supported by mural cells in three-dimensional culture. Injection of Flk1+ cells into chick embryos showed that they can incorporate as endothelial and mural cells and contribute to the developing vasculature in vivo. Our findings indicate that Flk1+ cells can act as 'vascular progenitor cells' to form mature vessels and thus offer potential for tissue engineering of the vascular system.
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              Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney.

              Development of the mammalian kidney is initiated by ingrowth of the ureteric bud into the metanephric blastema. In response to signal(s) from the ureter, mesenchymal cells condense, aggregate into pretubular clusters, and undergo epithelialisation to form simple epithelial tubules. Subsequent morphogenesis and differentiation of the tubular epithelium lead to the establishment of a functional nephron. Here we demonstrate that Wnt-4, a secreted glycoprotein which is required for tubule formation, is sufficient to trigger tubulogenesis in isolated metanephric mesenchyme, whereas Wnt-11 which is expressed in the tip of the growing ureter is not. Wnt-4 signaling depends on cell contact and sulphated glycosaminoglycans and is only required for triggering tubulogenesis but not for later events. The Wnt-4 signal can be replaced by other members of the Wnt gene family including Wnt-1, Wnt-3a, Wnt-7a and Wnt-7b. Further, dorsal spinal cord, which has been thought to mimic ureteric signaling in tubule induction induces Wnt-4 mutant as well as wild-type mesenchyme suggesting that spinal cord derived signal(s) most likely act by mimicking the normal mesenchymal action of Wnt-4. These results lend additional support to the notion that Wnt-4 is a key auto-regulator of the mesenchymal to epithelial transformation that underpins nephrogenesis adding another level of complexity in the hierarchy of molecular events mediating tubulogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                3 June 2013
                : 8
                : 6
                : e64843
                Affiliations
                [1 ]Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
                [2 ]Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
                Wellcome Trust Centre for Stem Cell Research, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RM TM HI HO. Performed the experiments: RM. Analyzed the data: RM SF SY KH YM. Contributed reagents/materials/analysis tools: RM SF SY KH YM. Wrote the paper: RM.

                Article
                PONE-D-12-37805
                10.1371/journal.pone.0064843
                3670839
                23755150
                67479c71-3d97-4d23-be51-a0d689e6a1ab
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 November 2012
                : 18 April 2013
                Page count
                Pages: 10
                Funding
                This work was supported in part by Grant-in-Aid for Scientific Research (KAKENHI, 23890203, 21591038, 24591211) and a grant from Daiwa Securities Health Foundation ( http://www.daiwa-grp.jp/dsh/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Stem Cells
                Embryonic Stem Cells
                Cell Differentiation
                Immunology
                Immunologic Techniques
                Immunofluorescence
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Cellular Types
                Stem Cells
                Embryonic Stem Cells
                Cytometry
                Flow Cytometry
                Medicine
                Nephrology
                Developmental Nephrology

                Uncategorized
                Uncategorized

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