熊本大学発生医学研究所／ P15-16 【英訳】Division of Stem Cell Research

Cell Modulation

Through the comprehensive analysis of the initialstage of cell differentiation
We aim to elucidate basic mechanisms and applythat knowledge
To the development of next-generation researchon intractable disease
In order to effectively elucidate the mechanisms by which
abnormalities occur in cells, we must first clarify what
happens in the initial stages of stem cell differentiation.
In his research, Dr. Takumi Era uses embryonic stem (ES)and induced pluripotent stem (iPS) cells to examine thebasic mechanisms of embryogenesis,
with a view to establishing next-generation therapies.

Understanding the normal toexamine the abnormal

cancer and other diseases,” says Dr. Era.

Disease-derived iPS cells
speed up the pace of research

The transplantation of hematopoietic stem cells has been
established as the treatment for hematologicalmalignancies. Despite this, there are many problems instem cell therapies because of the difficulties in cell
preparation. This has led to increasing interest in thepotential output of research that makes use ofpluripotent cells (ES and iPS cells), which have thecapacity to differentiate into a number of different typesof cell.

In his research thus far, Dr. Era has succeeded ininducing ES cells to differentiate into mesenchymal stem
cells and endoderm stem cells. The potential scope of his
research has also been expanded greatly by the discoveryof iPS cells.
“In order to elucidate the mechanisms of pathologicalevents in diseases, we must have access to the cells ofpatients with the disease in question. The number ofpatients with intractable diseases, however, is very few, so
researchers who want to study certain diseases have
hardly access to the cells of relevant patients,” explains
Dr. Era. “What is more, for neurological diseases there
were certain challenges in extracting the cells required
for research.” The emergence of iPS cells, however, hassolved many of these problems. iPS cells, artificiallyengineered pluripotent stem cells, are generated fromalready differentiated somatic cells such as skin andblood cells by recovering pluripotency (meaning they
can differentiate into a number of different cell types).
Cells derived from the patient are used to generate iPS
cells, and these cells can then be induced to differentiate
into different types of cell again. By studying thisprocess, it is possible both to understand themechanisms that cause disease to occur and to makediscoveries that may lead to the development of new
therapies. “iPS cells are usually generated from somatic
cells such as fibroblastic cells in the human skin, andtoday it has even become possible to generate iPS cells
from peripheral blood cells.” iPS cells contain withinthem great potential, which Dr. Era seeks to harness inorder overcome the present obstacles preventing furtherWhen Dr. Era was working as a hematologist, he became
interested in the question of how blood cells becomecancerous, leading to leukemia. He then chose to pursue
this curiosity, taking up a path of stem cell research.
“Blood cells can be generated from embryonic stem cells(ES cells), a type of pluripotent cell, under a propercondition. My belief is that, in order to understand how
abnormal cells are generated, we must first focus on theinitial stages of stem cell differentiation. So I started to
study the mechanisms of ES cell differentiation intoblood cells.”
The development of the tissues and organs partiallyinvolves the same molecular mechanisms as seen in the
carcinogenesis. With development, however, the cells
proliferate in an orderly manner, while cancer cells
proliferate chaotically. “My research attempts to answer anumber of questions, such as what are the differences in
the mechanisms between driving orderly and disorderly
proliferation, and how are abnormal cells, which go on tocause disease, able to develop? If the processes in theinitial stages can be clarified, then it may well be possible
to develop methods of cellular regeneration, which inturn may have useful applications in the treatment ofProfessor

Application of basic research findings to thedevelopment of new therapies

Takumi Era
tera@kumamoto-u.ac.jp●Era T. Pluripotent stem cell as a source of mesenchymal stem
cell. Inflammation and Regeneration. In press.
●Hamasaki M, Hashizume Y, Yamada Y, Katayama T, Hohjoh H,Fusaki N, Nakashima Y, Furuya H, Haga N and Era T.
Pathogenic mutation of ALK2 inhibits iPS cell reprogrammingand maintenance: mechanisms of reprogramming and strategy
for drug identification. Stem Cells, 30:2437-2449, 2012.
●Kitagawa M, Takabe A, Ono Y, Imai T, Nakao K, Nishikawa SI
and Era T. Phf14, a Novel Regulator of Mesenchyme Growth via
Platelet-derived Growth Factor (PDGF) Receptor-α. J. Biol.
Chem. 287: 27983-27996, 2012.

15Dr. Era is involved in the project as a member of theresearch unit tasked with developing methods for theefficient provision of biological specimens. “Theestablishment of this sort of bank is of great significancefor research that focuses on intractable diseases. I hopethat it will help us relieve patients with intractablediseases, even if it is just one at a time.”
At the same time, Dr. Era notes the importance of failure
in research. “If you are able to accept that some of yourresearch will fail, that frees your mind to discover things
that you might otherwise never even have considered. Of
course, knowledge is extremely important, but as aresearcher you also need to have experienced failure.
Anyone thinking of choosing a career in research should
be aware that it is willingness to take on a challenge thatis most important in research, and should build up yourexperience and your ability to think creatively.”

iPS (F2)iPS F1-1

Gene analysis

iPS F2-1

iPS (F4)

Gene expression ofdisease-derived iPS cells

iPS F4-1

Nanog

β-actin

Identify molecules causing malignant tumors

Development of therapies for lung fibrosis

SeV

Oct 3/4

nestedrelative expression

Oct 3/42

Sox2

SSEA4

Klf41.5c-Myc
TRA-1-60

1Effects of gene suppression on tumor growth
1Cancer cell lines

References

In 2009, the Rare Disease Bank was set up as part of aproject funded by the Japanese Ministry of Health,Labour and Welfare on rare and intractable diseases. The
role of the bank is to collect and store biologicalspecimens, such as patient blood, cells, and DNA. By
targeting 130 rare diseases, collection is conducted by a
dedicated research team, which works with medical
institutions to collect and store biological specimens andmedical data from patients. These resources are available
to universities and research institutes.

Characterization of disease-derived iPS cells

ProfileGraduated with a Bachelorﾕs degree from the Kumamoto
University School of Medicine, before going on to complete adoctoral degree at the Graduate School of Medicine at the sameuniversity.
Worked as an attending physician at the Second Department ofInternal Medicine, Kumamoto University School of Medicine, thenwent on to take up a research assistant role at the ResearchInstitute for Microbial Diseases at Osaka University.
Held a post-doc position at the Howard Hughes Medical Institute,
University of California, Los Angeles, then joined the RIKEN
Center for Developmental Biology as a researcher. Worked as anattending physician in the Division of Hematology, Department ofInternal Medicine, Kumamoto University Hospital.
In 2008, Dr. Era became a professor at the Institute of MolecularEmbryology and Genetics, Kumamoto University.

The Rare Disease Bank-1
F4S
iP F4obr
Fi -1
F2S
iP F2obr
Fi -1
F1S
iP F1obr
Fi edctfeinS
V- l iPSe troonC

IntermediatestagesCell separation andpurification

research into intractable diseases and the establishmentof new therapies. “This has really widened the scope ofresearch for scientists. If we can get more people working
on unlocking the secrets of intractable diseases, then I
think we will see real advancements in medicine”.

0.5

Nanog
Gdf3

day0day1

day7

Sal4f

AP

P<0.01
0.8

Rex1

0.6

Dnmt3b0.4

Application of iPS cells to research on intractable diseases

0.2

control

bleomycin

cbleomycin+APA5

Generation of disease-derived iPS cells.

0SY5Y

TGW

CHP

NBLS IMR32 SKNSH

NB6

Oct3/4
Sox2
Klf4
cMyc

NB19

Relative growth rate

Developing RNAdrugs for cancers

Developing antibody
drugs for lung fibrosis

Skin-derived
fibroblast

Establishing
iPS cellsIntermediate-stage cell

Target cells

Genetic analyses of cells in thesestages will provide insight into
pathogenesis and new drug development.

16