熊本大学発生医学研究所／ P13-14 【英訳】Division of Stem Cell Research

Cell Differentiation

Tackling the mysteries ofhematopoietic stem cells
Together with researchon the blood vessel development,
we close in on the truth behind themechanisms of their origin and maintenance
Scientists have been aware of hematopoietic stem cells (HSCs),a representative type of stem cells, for a relatively long period.
But we still do not know where they come from or
how they are maintained within the body.
Dr. Ogawa seeks to elucidate the nuts and bolts behind HSCs,
and to develop regenerative techniques for
HSCs that may one day be developed into
life-saving clinical applications.

Professor

Minetaro Ogawa
ogawamin@kumamoto-u.ac.jp

The undiscovered origins of HSCs
Hematopoietic stem cells are found within bonemarrow, and they are ultimately responsible for bloodformation. These cells differentiate into white bloodcells, red blood cells, lymphocytes, and all the othertypes of cell that make up our blood, and further serve
to keep the respective levels of those cells at therequired constant. They are a representative type ofstem cells, long since known to science. “Having said
that, we do not actually know where HSCs themselves
are generated, nor do we know the sort of control
mechanisms in place to keep them self-renewing andmaintained within the body,” explains Dr. Ogawa.
In developing fetuses, blood formation occurs before
the generation of HSCs. In this stage, white blood cells,
red blood cells, lymphocytes, and other types of blood
cell are produced from endothelial cells; we know thatthese cells do not pass through HSCs in order tobecome blood cells. Today, it is possible to produce
endothelial cells from embryonic stem (ES) cells,
cultured in petri dishes, and then to generate blood
cells from the endothelial cells. But those are not really
HSCs, of course. Dr. Ogawa is keen to point out that, sofar, scientists have only succeeded in producing
hemogenic endothelial cells, not true HSCs.
“We know that if you introduce a certain gene into an
ES cell, then you end up with something that is ‘quite
like’ an HSC. But that does not mean it is any good atwhat it is supposed to do, and we also know that these
HSC will not differentiate into lymphocytes,” explains
Dr. Ogawa. “There are still many mysteries to be
uncovered about the generation mechanisms of HSCs.
One of the core topics of my research is shedding lighton these mechanisms and looking to see how they
could be put to use in HSC regeneration techniques.”

References●Sakamoto, H., Tsuji-Tamura, K. and Ogawa, M. Hematopoiesis
from pluripotent stem cell lines. Int. J. Hematol. 91: 384-391,
2010.
●Tsuji-Tamura, K., Sakamoto, H. and Ogawa, M. ES celldifferentiation as a model to study cell biological regulation ofvascular development. Embryonic Stem Cells: The Hormonal
Regulation of Pluripotency and Embryogenesis ed. CraigAtwood, ISBN 978-953-307-196-1, INTECH, Vienna, Austria,
2011, pp581-606.

13At Dr. Ogawa’s laboratory, his team is working on astudy of the self-renewal mechanisms of HSCs. It is notpossible for HSCs to produce blood cells without there
being an adequate supply of HSCs, so these cells
implement an iterative process of self-replication, all thewhile maintaining their pluripotency, before
differentiation into blood cells. The team is trying toestablish how this self-renewal is controlled to ensurethat the body never runs out of its supply of HSCs.
At present, although bone marrow transplantation isconducted as a treatment for leukemia, the process ismarred by the lack of matching donors. If it became
possible to use ES cells or induced pluripotent stem
cells, derived from the patient’s own body, to produce
HSCs, to use genetic therapy to return these HSCs to anormal state, and to re-introduce them to the patient’sbody; then the level of treatment available for blood
diseases like leukemia would soar. “That is a real
motivator for me; we need to figure out and fully
understand where these HSCs come from and how
they control their self-renewal,” says Dr. Ogawa. “Thenext stage is to develop perfect conditions—carefullydeveloped and chemically defined—under which we
can generate ‘real’ HSCs with real HSC functionality.”This determination to uncover the secrets behind theorigins of HSCs, and then to take that knowledge anduse it for the betterment of medicine, is an excellent
example of the commitment seen in so many biologists
engaged in basic research.

Toward the truth behind bloodvessel formation mechanisms

ES cell differentiation into blood and vascular cells

Elsewhere, Dr. Ogawa and his team are looking at
cel l-shape cont rol mecha n isms i n va sc u la r
endothelial cells, with a particular focus on Foxo1 asa transcription factor that plays an important role invascular formation.
When Foxo1-deficient ES cells are cultured and used toproduce blood vessels in a petri dish, the resulting
endothelial cells show abnormalities in shape. They areunable to regulate their shape through elongation, andinstead take on abnormal forms. The Foxo1-deficientmouse model resulted in embryonic lethality as a resultof abnormalities in blood vessel formation. “Thisindicated that Foxo1 has a role to play in regulating theexpression of other genes related to the elongating
function of vascular endothelial cells,” explains Dr.
Ogawa. “We then looked at what other genes control
Foxo1, and discovered a candidate gene that encodes an
enzyme that worked to balance the phosphorylation ofcertain proteins. Without Foxo1, the candidate gene
may not be expressed, which means that this same genemust be one of the genes related to regulation of themorphology of cells. Dr. Ogawa and his team have alsoestablished t hat if t his gene is inser ted into
Foxo1-deficient endothelial cells, the cells will regain
the ability to elongate normally. Their work in this area
continues.
Blood vessels form normally when vascular endothelial
cells assemble with vascular smooth muscle cells, butwhen Foxo1 has been knocked out, the endothelial cells
and smooth muscle cells fail to assemble, remaining
separate instead. Dr. Ogawa and his team believe that
this is because Foxo1 controls the gene that would
otherwise facilitate the assembly of the two cells types;
their work continued in an effort to prove thishypothesis.

Generating hematopoietic cells from ES cells？

Primitive erythrocyte

ES cell

ES cellProfileAfter graduating with a Bachelor s degree in pharmaceuticalchemistry from the Faculty of Pharmaceutical Sciences atKanazawa University, Dr. Ogawa entered the Graduate School of
Pharmaceutical Sciences at the same university, where heobtained his Master s degree, and later, Doctoral degree bythesis only.
He worked as a research assistant at the Institute of Molecular
Embryology and Genetics, Kumamoto University Medical School,
as well as Faculty of Medicine, Kyoto University. He held aresearch fellowship at the Basel Institute for Immunology in
Switzerland, then worked as an associate professor at theGraduate School of Medicine, Kyoto University. In 2002, hereturned to the Institute of Molecular Embryology and Genetics,Kumamoto University as a professor.

Aiming for HSC generation undercrystal-clear conditions

Mesodermal cell

Definitive blood cells

Vascularendothelial cellElongation of endothelial cells

Hematopoietic
stem cell

Vascular formation from ES cells

Cardiomyocyte

Vascular smooth muscle cell

Vascular endothelial cell

Teaching Staff
Assistant Professor

Assistant Professor

Hiroshi Sakamoto

Kiyomi Tamura

I am currently conducting stem cell researchusing hematopoietic stem cells. I am always
ke en to adopt the latest te chn ology into myresearch and combine it with more traditionalm eth o dological appro aches with the aim ofdeveloping new ideas and concepts in stem cellresearch.

My main research topic is the clariﬁcation of mechanisms of bloodvessel formation. Blood vessel formation is very closely linked to theadvancement of a number of diseases, including cancer and chronicinﬂammation. I am trying to establish what mechanisms are in place toregulate blood vessel formation, and ways in which we might be able toregenerate and control blood vessels. I hope that this research willcontribute to the development of therapies for such diseases.

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