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Researchers for the future

Trying to regenerate the kidney, pancreas and liver (2)-All 2 episodes-

Dr. Kenji Osafune

Interviewer :
Then, you came back to Japan and to the kidney, didn't you?

Osafune :
I was looking for a post in Japan, and fortunately, Dr. Yamanaka offered me a post at the Center for iPS Research and Application (CiRA), Kyoto University. I was studying only the kidneys for one year and a half, then began to deal also with the pancreas when my research began to go well, and extended my research to the liver.
For the pancreas, we have a clear idea of clinical application. We have already a technique for treatment of diabetes, which is islet transplantation for which islet tissues are transplanted through a catheter inserted in the liver. If we will be able to regenerate islet cells efficiently, we will then be able to treat patients with type I diabetes in collaboration with doctors in transplantation surgery or internal medicine for diabetes.

Interviewer :
You are working at CiRA since three years, and what is your greatest achievement?

Chart:Strategy for inducing differentiation of iPS cells into kidney cells.

Strategy for inducing differentiation of iPS cells into kidney cells.
(large view(PDF)

Osafune :
It is that I have established a basic technique for inducing differentiation of iPS cells into certain cells called intermediate mesoderm that is an intermediate stage crucial for kidney generation from iPS cells. This is a first and important step to kidney generation, I can say. I am the first in the world who have done it. From the intermediate mesoderm, only three organs develop, which are the kidney, adrenal gland and gonad, and if we will be able to suppress its differentiation into the latter two organs, we will get only kidney cells at high efficiency. We will be able to do it in two or three years.
For the next steps, we do not know yet how to induce differentiation into kidney precursor cells, and are looking for factors that will set off differentiation in this direction. It is myself who demonstrated for the first time, when I was a graduate student, that there are kidney precursor cells that are capable of differentiating into the renal tubule and the gromelurus.

Interviewer :
Which types of kidney cells will be more important in regenerative medicine?

Osafune :
It is said that there are twenty types of cells that constitute the kidney, among which proximal renal tubule cells that are involved in many physiological functions of the organ seem to be most important. If we will be able to prepare this type of cells, then we will be able to use the cells not only for development of treatments with transplantation but also for a "biological" artificial organ in which the cells are attached onto the hollow fibers of haemodialyzers.

Interviewer :
It is to say that there will be ex-vivo applications, isn't it?

Osafune :
Yes. We can use these cells for building disease models. We have established iPS cell lines from somatic cells of seven patients with ADPKD, and if we will be able to differentiate these iPS cells into renal tubule cells, we will then be able to build in vitro models of the disease. And also these cells will be useful for drug development.

Interviewer :
What was the point definitive for your success in obtaining the intermediate mesoderm?

Osafune :
In the beginning, I tried to establish human iPS cell lines in which the marker transcription factors are dyed with a fluorescent protein introduced into the corresponding alleles to visualize expression of the target cells and monitor the level of conversion. However, it was technically difficult to introduce a fluorescent protein into the genome of human iPS or ES cells. We then developed a new technique for facilitating introduction of the protein, and established a system in which we are able to monitor the level (%) of conversion into the target cells. We have made a patent application for this technique. This was the point. Using this system, we tried combinations of many growth factors and compounds to find the best one and developed an efficient technique for induction of differentiation.

Interviewer :
You did make many trials and errors before finding the efficient technique for inducing differentiation, didn't you?

Osafune :
We tried more than forty growth factors one by one, and found the best combination of three factors among them. And also, we collected about fifty thousand low molecular weight compounds from various sources, and screened them by the high throughput screening method, to find certain compounds that induce differentiation of human iPS cells into the intermediate mesoderm efficiently. I am preparing an article to submit to a journal, and applying for a patent.

Interviewer :
What is the advantage in using low molecular weight compounds?

Osafune :
To prepare growth factors, we use E. coli culture for producing recombinant proteins and purify the culture broth to obtain the factors. We have many steps to do and it costs much. In addition, the efficacy of the factors varies with preparation lots. In contrast, if we use low molecular weight compounds, they are uniform in efficacy and can be synthesized biochemically in large quantities. Thus, they cost less, and some of them are available at a price one thousandth or one ten-thousandth of that of growth factors.
For induction of differentiation into the pancreas and the liver, I have found so far one compound for each organ by the same approach. This approach is one that I already used when I was at Harvard University, and I found that the compound Indolactam V was useful for inducing one step of differentiation from pluripotent stem cells into pancreatic beta cells. I suppose that we will be able to induce all the steps of differentiation, using low molecular weight compounds.

Interviewer :
What will you have achieved in ten years, in the field of your research now?

Osafune :
My goal in ten years is that we will be at a stage where we will be able to use transplants of beta cells or islet cells prepared from iPS cells at the clinical level. If we use these cells for artificial organs, we do not have to care about the risk of carcinogenesis of the cells, and it will be easier to prepare kidney or liver cells from iPS cells with practically acceptable qualities in the near future. We will be able to develop cellular models of intractable diseases like ADPKD to find diagnostic markers or to screen drugs in a relatively short time.
There are some barriers to surmount in the field of research for regenerative medicine : the cells that we generate from iPS cells show only part of the functions of the target cells found in the body, and it is still difficult to regenerate a tissue or an organ from the cells that we prepare. How we will be able to solve the problems? This is what is always in my mind. The kidney, pancreas and liver are the organs for which there are large demands in clinical medicine, and I feel always encouraged in such a situation.

Photo:Members of Osafune Lab
Members of Osafune Lab

Interviewer :
Would you give advice to young scientists?

Osafune :
In this field of research for regenerative medicine, we are in a very exciting situation where we see large breakthroughs made one after another and what have been thought "common senses" are upset. I find it more and more interesting. You may hesitate or be anxious about your way to go, when you are young. I hope you will find soon what you will be really interested in, and will follow it without too much caring about your future. Who imagined that iPS cells would be generated? Nobody knows what will happen in the future. In the world of research, it happens that one day you make an unexpected step forward. It is important to continue your work.


Interviewer :
Furugori Etsuko
Interview date : January 17, 2012

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Dr. Kenji Osafune

Associate Professor, Department of Cell Growth and Development, Center for iPS Cell Research and Application, Kyoto University

In 1971 he was born in Hyogo Prefecture. In 1996 he graduated from Faculty of Medicine, Kyoto University. He was a clinician in nephrology. In 2003 he finished the doctoral course at the Graduate School of Science, The University of Tokyo. He was granted a doctor degree in science. From 2000 to 2005 he was studying development and regeneration of the kidney under Prof. Makoto Asashima at The University of Tokyo. From 2005 to 2008 he was working on kidney regeneration from human ES and iPS cells under Prof. Douglas A. Melton at Harvard University. From 2008 he is working at the Centre for iPS Research and Application, Kyoto University.

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