July 2013
Vol.
2

Center for iPS Cell Research and Application, Kyoto University

CiRA
Newsletter

Shinya Yamanaka

CiRA International Symposium 2013 Report

CiRA International Symposium 2013 was Held

The CiRA International Symposium 2013 was held on March 11 and 12 at the Kyoto University Clock Tower Centennial Hall. About 550 researchers, students and journalists from 17 countries took part in the two-day event.

On the March 11, filled with fresh air celebrating the advent of spring, hundreds of researchers gathered at the venue to attend the symposium, with the theme, “Raising the Next Generation of Stem Cell Research.” Fourteen distinguished scientists from Britain, Germany, Japan and the U.S. gave lectures on their latest studies in the areas of stem cell and nuclear reprogramming.

The lectures were based on two main themes; one was the study concerning nuclear reprogramming, namely the fundamental technology for the generation of iPS cells, and the other was for the development of new therapies for intractable diseases using stem cells such as the iPS cell.

The lecturers on nuclear reprogramming mechanisms were given by Dr. Konrad Hochedlinger of Harvard University, Dr. Richard A. Young of the Whitehead Institute for Biomedical Research, Dr. Austin Smith of the University of Cambridge, Dr. Hans R. Schöler of the Max Planck Institute for Molecular Biomedicine, and Dr. John Gurdon of the University of Cambridge, who won the 2012 Nobel Prize for Physiology or Medicine, jointly with Dr. Shinya Yamanaka.

The scientists who spoke about their studies on the development of therapies using stem cells were; Dr. Ian Wilmut of the University of Edinburgh, Dr. Deepak Srivastava of the Gladstone Institute of Cardiovascular Disease, Dr. Kevin C. Eggan of Harvard University, Dr. Amy Wagers of Harvard University, Dr. Hideyuki of Keip University, Dr. Hiromitsu Nakauchi of the University of Tokyo, Dr. Mahendra Rao of the NIH and CiRA Director Shinya Yamanaka.

The second day’s program included a special lecture titled “Development of Hematopoietic Stem Cells: My Final Scenario” by Dr. Shin-ichi Nishikawa, deputy director of the RIKEN Center for Developmental Biology, who was retiring at the end of March. The “Topics from the FIRST Program,” in which the program researchers, Lecturer Masato Nakagawa and Associate Professor Asuka Morizane, reported the latest achievements in the project led by Dr. Yamanaka.

This year, poster sessions with 82 participants were also held, through which research groups from various countries presented their latest data and exchanged opinions among the participants in the symposium.

Dr. Yamanaka and Dr. Gurdon

With the participation of the eminent researchers, including the 2012 Nobel Prize laureates Dr. Yamanaka and Dr. Gurdon, this symposium received participant applications for well over the 500-seat capacity.

At the press conference with Dr. Yamanaka and Dr. Gurdon held immediately prior to the symposium’s opening, Dr. Gurdon said, “It was about 50 years ago that I first visited Japan, and I am delighted to be here again,” while Dr. Yamanaka stated his intention to further focus on his research activities by saying, “It has been very difficult to return to my normal working schedule as I have had to attend so many events since I received the Nobel Prize. But I would like to concentrate on my research by taking this symposium as an opportunity”.

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CiRA Cafe

The CiRA Cafe was Held

Dr. Ian Wilmut
Dr. Ian Wilmut

The first CiRA Cafe FIRST in English was held at the entrance hall of the CiRA research building was held on March 10, with Dr. Ian Wilmut as the guest speaker. While 25 people, including a few foreign residents in Japan, took part in the event, Dr. Wilmut gave an explanation of the general background and development of his study, from the cloned sheep Dolly to iPS cells in easy-to-understand English. Freelance science journalist Shigeyuki Koide served as the moderator. This event gave the participants with a rare opportunity to not only learn about the research activities of Dr. Wilmut but also to come into contact with his personality.

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Research findings (Alzheimer's disease)

Aiming for the Development of New Therapy for Alzheimer’s Disease in the Aging Society

The paper by a group led by doctoral student Takayuki Kondo and Associate Professor Haruhisa Inoue, both of CiRA’s Department of Clinical Application, was published online by the science journal Cell Stem Cell. We asked Dr. Inoue about the research findings.

Would you explain about Alzheimer’s disease?

Alzheimer's disease (AD) is a progressive dementia with memory disorder that is most common in senile dementia patients. The number of such patients is on the rise as Japan has become the aging society. The disease develops in patients of middle-age or older, and begins to interfere with daily life as it gradually advances, and finally causes patients to have difficulty in communicating.

Its pathological characteristics include accumulation of protein called senile plaques in the brain. Although it is known that the principal element of the plaques called beta amyloid (Aβ) is generated by cutting off a part of the amyloid precursor protein (APP), there are several theories concerning how it relates to the clinical state in human brains, and no theories are yet conclusive.

What are the difficulties in advancing research on Alzheimer’s disease?

Before iPS cell technology was developed, researchers could not obtain neural cells from patients to analyze their clinical state. We were only able to use cells that had already developed the disease, which made it impossible for us to explore the process before its onset.

Today, we are able to study the clinical conditions by generating iPS cells from AD patients’ somatic cells such as skin cells and then differentiating them into neural cells. However, as the symptoms of Alzheimer’s disease develops as people get older, we needed to be creative to reproduce its clinical conditions in a Petri dish.

What was the study subject for this paper?

We generated iPS cells from Alzheimer’s disease patients; two familial AD patients (early onset) and two sporadic AD patients (late onset) and differentiated them into neural cells. When comparing these neurons with those of healthy persons, Aβ oligomer deposits in strands consisting of a dozen Aβ were observed in the neural cells of one familial AD patient and one sporadic AD patient. Simultaneously, endoplasmic reticulum- and oxidative-stresses occurred in the cells through the malfunction of protein foldings. We also found that these stresses could be reduced by adding a low level of docosahexaenoic acid (DHA) to these neurons.

What is the significance of the research findings?

In the past, there were doubts surrounding the feasibility of reproducing a late-onset disease in a Petri dish. Our study demonstrated that it is possible. The development of symptoms in later age may in reality be because neurons are protected by the cells surrounding them.

Aβ deposits outside the neural cells were generally known as one of the pathological features of AD. Our study has also revealed that among AD patients, some have Aβ deposits that increase outside the cells, while in others they increase inside the cells, and also that the stress caused by the intracellular Aβ deposits can be reduced by DHA.

We believe that there is a potential for predicting the development of AD in patients and determining the type of clinical state, by further advancing analysis. Furthermore, we anticipate that the potential use of iPS cell technology will contribute to the so-called preemptive medicine which applies treatment based on every type of clinical state prior to its onset.

Photo A<em>β</em> oligomer in neurons
Photo Aβ oligomer in neurons

Aβ deposits can be observed as yellow dots, which cannot be found in the neurons generated from the cells of healthy persons.
Yellow: Aβ oligomer, Blue: Cell nuclei, Red: Neurons

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Research findings (Kidney diseases)

Regeneration of a Subset of the Kidney Structure, Using Human iPS Cells

The research group led by doctoral student Shin-ichi Mae and Associate Professor Kenji Osafune, both of the Department of Cell Growth and Differentiation at CiRA, has succeeded in differentiation induction of human iPS cells into intermediate mesoderm, the precursor of kidney and gonad, in a highly efficient differentiation method. This marked a great stride toward kidney regeneration. The findings were published online in the journal Nature Communications. We asked Dr. Osafune about the research findings.

How difficult would it be to regenerate the kidney?

Compared with other organs, the kidney has a very complicated structure combining numerous types of cell. It also plays various roles, including waste disposal as urine, control of blood pressure, and stimulation of red blood cell production.
Once the kidney is damaged, it is irreparable in most cases. Patients with kidney diseases are obliged to live on dialysis when their malfunction progresses due to the accumulation of damages. The number of Japanese dialyzed patients exceeds 300,000, while dialysis treatment accounts for six percent of the total national medical expenses. Much is expected therefore of researches concerning kidney regeneration.

What is intermediate mesoderm?

Although experiments have been carried out to differentiate iPS cells or embryonic stem (ES) cells into kidney cells, no technology to induce them has yet been established. Past developmental biology studies have shown that kidney cells are generated from intermediate mesoderm. To induce intermediate mesoderm from iPS/ES cells with high efficiency will be a first vital step toward the induction of kidney cells.

What has been achieved by this research?

First, we established a method to easily ascertain whether differentiation of iPS/ES cells into the target intermediate mesoderm cells has been achieved. By applying this method, we found the most effective way of differentiating human iPS/ES cells into intermediate mesoderm. We succeeded in generating intermediate mesoderm through a highly efficient process by making BMP7 and activin A, growth factors, and low-molecular compound CHIR99021 stimulate the cells.

When the generated intermediate mesoderm and kidney cells of a mouse fetus were co-cultured, some of the cells formed tubular-shaped cells, showing that they are capable of producing a part of renal three-dimensional structures.

What is the significance of the research findings?

As intermediate mesoderm differentiates into only three lineages of kidney - adrenal cortex and gonad cells, the establishment of the efficient method to produce intermediate mesoderm is a vital step toward the realization of kidney regeneration. In the future, it will be necessary to develop a method which enables the differentiation of intermediate mesoderm into kidney cells in an efficient manner. In addition to the kidney, this method may be applied to the regeneration of the adrenal cortex and gonad is also expected.

Figure 1
Directed differentiation steps from human iPS cells into kidney cells This shows that the intermediate mesoderm generated in an efficient induction method can be differentiated not only kidney but also adrenal cortex and gonad cells.

Figure 2
Formation of a renal tubular structure in some cells induced from intermediate mesoderm.
The blue indicates cell nuclei, and orange (mixture of red and green) renal tubules induced from intermediate mesoderm, showing their tubular structure.
Green: Human mitochondria (i.e. human intermediate mesoderm-derived cells)
Blue: Nuclei
Red: LTL (marker genes of renal tubular cells)
All white bars represent 50 μm.

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Stockpiling of iPS cells

Stockpiling of iPS Cells for Regenerative Medicine — Q&A

Q.What is the iPS Cell Stock Project for Regenerative Medicine at CiRA?

A.It is a plan to stockpile iPS cells produced at a cell processing facility at CiRA, called the Facility for iPS Cell Therapy or FiT, using blood or skin cells from healthy people with specific HLA types (HLA homozygote donors). By making them in advance, high quality iPS cells can be expeditiously provided to medical and research institutions in Japan and overseas.

Q.What is HLA?

A.HLA stands for Human Leukocyte Antigen, the major histocompatibility complex in humans, which are like the blood types in white blood cells. HLA are distributed not only in leucocytes but also in nearly all cells and body fluids while functioning as vital molecules concerning the human immune system.

When we receive cell or organ transplants from a donor with an HLA type different from our own, our body recognizes them as foreign, thereby resulting in rejection by the immune system. It is therefore important to mitigate this rejection response by matching the HLA type as closely as possible for such transplants.

Q.When will the iPS cell stock become available for treatments?

A.We are aiming to start clinical studies or tests using stocked iPS cells within five years. After clinical studies begin, to establish a therapy using iPS cell technology, it will be required to document its safety and effectiveness for transplants, and to submit an application for its use to the government. As things stand today, it will take several years to obtain approval, so we expect that it will take at least 10 years from now before the cells are used as treatments in medical institutions.

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Editorial Info

Publisher & Editor
CiRA International Public Communications Office
Email:cira-pr@cira.kyoto-u.ac.jp

Design & Photography
CiRA international Public Communications Office

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Information Media Design INC.
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This newsletter is produced with the support of the Funding Program for the World-Leading Innovative R&D on Science and Technology (FIRST Program).

Copyright © 2013 Center for iPS Cell Research and Application, Kyoto University
No part of this publication may be reproduced by any means under any circumstances without written permission of the Center for iPS Cell Research and Application, Kyoto University.

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