Press Release
February 14th, 2007
Research group headed by Associate Professor Takashi Tsuji of the Tissue
Engineering Research Center, Tokyo University of Science, succeeds in
developing artificial “organ (tooth) regeneration” technology
– Announced in online version of US scientific journal “Nature Methods”
13:00hrs (Eastern US Time), Feb. 18th –
Substantial advance in the development of next-generation
“organ replacement regenerative therapies”
A research group led by Takashi Tsuji (Associate Professor in the Department of Biological Science
and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science) has succeeded
in developing new cell manipulation technology whereby the germs that form organs can be artificially
recombined from a single cell. Tsuji is a research team member in “Priority Domain Research:
Bio-engineering (Domain Leader: Professor Toshio Fukuda of Nagoya University)”, a Grants-in-Aid for
Scientific Research Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
at the TUS Tissue Engineering Research Center (a MEXT Academic Frontier Research Center). The new
technology has potential for application to artificial “tooth regeneration” and “hair regeneration”. In
transplantation experiments using the tooth as a model, “regenerated teeth” were shown to grow normally in
the extracted tooth cavity of an adult mouse. The research also proved, for the first time in the world, that the
germs of artificial organs contain nerves and can grow in the target locus in the adult host, since there are
blood vessels and nerves inside the regenerated teeth.
This outcome is expected to substantially advance the development of “organ replacement regenerative
therapies”, which have potential as next-generation regenerative therapies for replacing diseased or damaged
organs with artificially engineered organs. Specifically, it will not only promote “tooth regenerative therapies”,
whereby organ germs of artificially engineered teeth are transplanted into the oral cavity to grow “3rd
generation teeth”, and “hair regenerative therapies” following hair loss, but is expected to evolve into a wide
range of organ regeneration technologies for liver, kidneys and other organs.
This research outcome was the fruit of joint research with Masahiro Saitoh (Lecturer, Department of
Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry) and Professor
Yasuhiro Tomooka (Director, Tissue Engineering Research Center, Tokyo University of Science). It was
announced in an Advanced Online Publication of the US scientific journal “Nature Methods” at 13:00hrs
(Eastern US Time) on Feb. 18th, 2007. It is also due to appear in the March issue of the journal’s paper
version.
* See separate sheet for an outline of the research outcome.
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Reference Sheet
Background to the research
Regenerative therapies, the medical therapies of the 21st century, are now undergoing basic research
and clinical application.
Current regenerative therapies have developed with a focus on “cell transplant therapy using stem
cells”. In this process, stem cells that exist in vivo and ES (embryonic stem) cells produced by induced cell
division from specific cells in vitro are transplanted in vivo.
Next-generation regenerative therapies will be “organ replacement regenerative therapies”, whereby
diseased or damaged organs will be replaced with artificially engineered tissues and organs through cell
manipulation in vitro. There are good prospects for the development of basic technology to this end.
At present, however, research and development are concentrating on reflux type or implanted artificial
organs using in vivo materials, multilayering of cell sheets formed from single cell strains, and so on. There is
no technology for creating artificial organs with a tissue structure made of multiple cell strains.
Outline of the research outcome
In all organs, organ germs are first induced by the reciprocal action of epithelial cells and
mesenchymal cells in the embryonic stage, after which organs consisting of multiple cell strains divide and
grow through the continuous reciprocal action of these epithelial and mesenchymal cells.
The research group developed basic technology on the model of the tooth as an ectodermal organ. The
aim of this was to reconstitute organ germs from simplified cells by manipulating cells in vitro and then to
grow these artificial organ germs in vivo (Fig. 1).
An important issue in this process is how to recombine simplified epithelial cells and mesenchymal
cells via cell manipulation, and whether the reconstructed germs of artificial organs will grow normally in the
targeted locus of the adult host.
Epithelial tissue
Tooth germ
Organ culture (2-4 days)
Epithelial cells
Reconstituted tooth germ
Extracted tooth
Reconstituted tooth germ
Mesenchymal tissue Mesenchymal cells
Surgical procedure
Collagen gel
Transplanted under renal
cortex membrane (14 days) Regenerated tooth
Fig. 1
Transplanted into
extracted
tooth
cavity
Schematic diagram of the research method
The research group developed technology for simplifying and extracting epithelial cells and
mesenchymal cells from tooth germs (organ germs of teeth) that exist in mouse embryos, then reconstituting
the epithelial and mesenchymal cells separately in collagen gel in vitro under conditions of high density. The
group succeeded in growing multiple teeth with the same tissue structure and periodontium as normal teeth,
with “100% frequency” (Fig. 2a, b, c). They confirmed that this technology can also be applied to other
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ectodermal organs, i.e. hair follicles (whiskers), and that hairs (whiskers) can be grown from artificial hair
follicle germs engineered from simplified epithelial and mesenchymal cells extracted from hair follicles (Fig.
2d).
a
Fig. 2
b
c
d
Teeth and hair (whisker) grown from artificially reconstituted organ germs
(a)
Regenerated incisor tooth grown dystopically in vivo from an artificial tooth germ
(b)
Regenerated incisor tooth grown by culturing an artificial tooth germ in vitro
(c)
Regenerated molar tooth grown by culturing an artificial tooth germ in vitro
(d)
Hair (whisker) grown dystopically in vivo from an artificial hair follicle (whisker) germ
Whether the germs of artificial organs will grow in the target locus of the adult host is the key to
creating the “replacement regenerative therapies” of the future. Another major issue in this respect is whether
nerves can be made to penetrate organs grown in this way, for the organs to fulfil their proper functions in
vivo. Until now, however, there have hardly been any reports on the growth of artificial organs. The research
group transplanted organ germs of artificial teeth into the extracted tooth cavity of an adult mouse. The result
was that initial growth within the jawbone of the adult mouse was the same as for normal teeth, and it was
proved, for the first time in the world, that blood vessels and nerves exist inside regenerated teeth grown in
this way (Fig. 3).
Fig. 3 Regenerated tooth grown from an artificial
P
tooth germ in the extracted tooth cavity of an adult
mouse
ob
D
E
Bar; 500 μm
am
Bar; 100 μm
D:
Dentine
E:
Enamel
ob:
Odontoblast
a:
Ameloblast
p:
Pulp (endodontium)
This research outcome not only establishes technology for artificially engineering organ germs of
teeth and hair through cell manipulation, but could also assist in developing technology for creating a wide
range of organs, such as liver and kidneys. Specifically, it not only has potential for “tooth regenerative
therapies”, whereby organ germs of teeth are transplanted into the oral cavity to grow “3rd generation teeth”,
and “hair regenerative therapies” following hair loss, but is also expected to usher in the development of
next-generation “organ replacement regenerative therapies” for replacing diseased or damaged organs with
artificially engineered organs.
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The Tissue Engineering Research Center of Tokyo University of Science
The Academic Frontier Promotion Project of the Ministry of Education, Culture, Sports, Science and
Technology is one of the Ministry’s projects designed to promote advanced scientific research in private
universities. It selects “Academic Frontier Research Centers” – outstanding research institutes that have
amassed an excellent track record in research and whose research is expected to develop further in future –
and provides them with prioritized, comprehensive support to promote their research. The Tissue
Engineering Research Center consists of a Cell Control Engineering Division and a Plant Life Engineering
Division. Its purpose is to develop basic technology for regenerative therapies and globally recyclable
products by researching and applying the mechanisms of growth and regeneration in living organisms.
・Address: 2641 Yamazaki, Noda City, Chiba Prefecture 〒278-8510 (inside the Research Institute for
Biological Sciences, Noda Campus of Tokyo University of Science)
・Director: Yasuhiro Tomooka (Professor, Department of Biological Science and Technology, Faculty of
Industrial Science and Technology)
■
Grants-in-Aid for Scientific Research Project of the Ministry of Education, Culture, Sports,
Science and Technology
“Priority Domain Research: System cell engineering (bio-engineering) by multiscale
manipulation”
In this Priority Domain Research, we carry out research on efficient expression control of genes in
cells, localized control for measurement and control of gene expression in cell clusters, and functional
control for inducing and expressing cell format and separation inside tissues. Using localized engineering
control methods and in close collaboration with bio and medical sciences, our research is based on multiscale
manipulation engineering technology across micro and nano domains, from nanometer to centimeter level.
・Research Domain Leader: Toshio Fukuda (Professor, Institute for Advanced Research / Graduate School of
Engineering, Nagoya University)
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