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January 18, 2013

Scientific paper on generation of paraxial mesodermal cells from iPS cells published in PLOS ONE

In a joint project with the research team of Professor Atsuko Sehara (Institute for Frontier Medical Sciences, Kyoto University), the research group of Hidetoshi Sakurai (lecturer, CiRA Department of Clinical Application) has established a method for efficiently inducing differentiation of mouse iPS cells(1) into the paraxial mesodermal(2) cells that are the progenitors of bone, cartilage, and skeletal muscle cells. The team also became the world's first researchers to successfully isolate paraxial mesoderm from human iPS cells. The scientific paper was published in the U.S. scientific journal PLOS ONE (October 24, 2012, issue). 

iPS cells have promising potential as a source of transplant cells for regenerative medicine and as a tool for drug-discovery research based on reproduction of disease states. But to fulfill this potential, iPS cells must first be differentiated into the target cell type. Numerous protocols for inducing differentiation have so far been developed using insights gained from developmental biology.

Meanwhile, findings from developmental biology research have shown that bone, cartilage, and skeletal muscle are differentiated from a cell type known as paraxial mesoderm. In humans, however, the path of differentiation from pluripotent stem cells such as iPS cells and ES cells(3) into paraxial mesoderm had not been clarified. 

Building on the results of previous research in mouse ES cells, the research project demonstrated that, in order to efficiently induce differentiation of paraxial mesodermal cells from mouse iPS cells, Activin A(4) signaling is essential in the initial stage of cell culture. It was also confirmed that paraxial mesodermal cells obtained using this method have the ability to differentiate into bone, cartilage, and skeletal muscle cells through cell culture, and the ability to regenerate skeletal muscle following transplantation into mouse. 

Up to now, there had been no method of distinguishing paraxial mesodermal cells from other human iPS cells, but the new research established that, like mouse cells, paraxial mesodermal cells can be identified from the expression of two marker proteins (PDGFRa and KDR). Specifically, in human cells cultured for approximately one week, a cell group that was positive for PDGFRa and negative for KDR showed high expression of marker genes specific to paraxial mesodermal cells. It was additionally confirmed that these cells had the ability to differentiate into bone, cartilage, and skeletal muscle. 

It is hoped that these findings will constitute the first step toward developing an efficient method for induced differentiation of bone, cartilage, and skeletal muscle cells. 

The present research was carried out in partnership between the Kyoto University Institute for Frontier Medical Sciences, CiRA, Kyoto University Graduate School of Biostudies, and Kitasato University School of Science.

Title of Paper

Hidetoshi Sakurai1,2*, Yasuko Sakaguchi1,3, Emi Shoji1, Tokiko Nishino2, Izumi Maki2, Hiroshi Sakai1, Kazunori Hanaoka4, Akira Kakizuka3, and Atsuko Sehara-Fujisawa1

Affiliated Institution
1Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
2Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
3Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
4Molecular Embryology, Department of Bioscience, School of Science, Kitasato University, Kanagawa, Japan


1) iPS cells
Induced pluripotent stem cells: pluripotent stem cells similar to ES cells but created by transducing specific factors into somatic cells. Their first ever successful generation was reported in 2006 by Professor Shinya Yamanaka's research team using mouse somatic cells. 

2) paraxial mesoderm
A cell population that appears in vertebrates at a certain stage of individual development and develops into supportive tissue including muscle, bone, cartilage, and skin. 

3) ES cells
Embryonic stem cells: ES cells are a type of pluripotent stem cell which can differentiate into the cells of any tissue type. Created by culturing cells extracted from the blastocyst at six or seven days after fertilization, their generation requires the destruction of the fertilized egg and therefore involves ethical issues. As they cannot be created from the patient's own cells, the risk of immune rejection is a concern. 

4) Activin
A type of hormone, found in the follicular fluid, that promotes the secretion of follicle-stimulating hormone. In the subsequent developmental process, it is known to be involved in promoting cell differentiation, and to have a wide range of other physiological activities including induction of hemoglobin synthesis and promotion of insulin secretion from the pancreas.

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