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The Challenge of Regenerative Medicine for the Central Nervous System

Researching the Generation/Regeneration Mechanisms of Nerve Cells: Applied Research into the Treatment of Spinal Cord Injuries

Professor, Department of Physiology, School of Medicine, Keio University Doctor of Medicine

Dr. Hideyuki Okano

Dr. Hideyuki Okano stands at the forefront of the pioneering research field of central nervous system regeneration. With multiple achievements in this field of the world’s highest standards, his research covers much ground. In addition to fundamental research clarifying the mechanisms behind nerve cell generation and regeneration, as an applied study his aim is to establish regenerative treatments for spinal cord injuries by utilizing stem cells. While challenging the common medical perception that the central nervous system of injured persons cannot regenerate, Dr. Okano’s research continues toward the aim of achieving regenerative treatments that are proven safe.

01.Ground-breaking Research Linked with the Treatments of Nervous System Diseases and Injuries

In recent years, the possibility of regenerative medicine is becoming more of a reality. Talk of ES Cells and iPS Cells have frequented the news, gathering the interest of the general public. Already, skin regeneration is, to an extent, being practically utilized, and research into the artificial manufacture of blood is advancing.

Within the various regenerative medicine sciences, the field that holds the most expectations while being the most difficult to achieve is the regenerative treatment of the central nervous system: the brain and spinal cord. This stems from the common perception of “once injured, any adult mammal cannot regenerate the Central Nervous System,” which has been long accepted in the medical world. The scientist who has destroyed this preconception with his groundbreaking discoveries is Dr. Hideyuki Okano, a Medical Professor at Keio University.

One research topic undertaken by Dr. Okano is the establishment of a system effectively derived from various neural cells (neurons) or glial cells (that make up the central nervous system structure) using neural stem cells. The above image is reproduced with permission from the Laboratory Website.

Dr. Okano made world history by being the first to discover the existence of neural stem cells in adult brains, providing evidence of the possibility of using these cells in the regeneration of the central nervous system. After researching the differential control mechanisms of neural stem cells using the drosophila fly in the 1990s, Dr. Okano has continued his research through studying the control mechanisms in the neural development of mice and the common marmoset – close in the order of primates to humans. Through his research, Dr. Okano is facing the challenge of solving the mysteries behind generative mechanisms of the central nervous system that use neural stem cells, ES and iPS cells existing in the adult brain.

The photograph on the left depicts a neural stem cell, the base of the nervous system. The photograph on the right is a neuron. (Photographs provided by: Assistant Professor Dr. Takehiko Sunabori, School of Medicine, Keio University)

Neurons and Glial cells that make up the nervous system are produced together from neural stem cells. Dr. Okano has not only clarified this process, but by explaining the fundamental mechanisms behind brain cell generation, he is attempting to link these discoveries with the treatment of injuries and disorders of the nervous system. The course of this research is gathering the attention of the entire world.


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02.Shedding the light on treating spinal injuries once thought to be impossible

A key target of Dr. Okano’s fundamental research is the treatment of spinal cord injuries. Spinal cord damage can be derived from anything as simple as an accidental fall or brought about by disease. Once the spinal cord is damaged, there is no natural regeneration to fix the problem. This can then lead to a partial or full loss of motor or sensory functions. According to the Ministry of Health, Labour and Welfare, every year over 5,000 people suffer from spinal damage caused by incidents, such as motor vehicle accidents, within Japan alone. A total of over 100,000 individuals suffer from paralysis.

This response renewed Dr. Okano’s sense of the sheer enormity and significance of his research.

The upper diagram depicts a fibroblastic cell grafted onto a damaged spinal cord. The lower diagram depicts a damaged spinal cord. (samples infused with buffer solution). The overall length is approximately 14 mm. After each sample is stained with HE, the samples are magnified. Photograph is synthesized using the “Image Stitching” Function of the all-in-one fluorescent microscope the BZ-X Series. (Photographs provided by: Dr. Osahiko Tsuji, Orthopedic Surgery, School of Medicine, Keio University)

Today, research into the medical treatment methods of spinal damage have now surpassed the initial steps of fundamental research. This research is now attempting to head toward the next stage of development.

“Our intention is to face an area never before attempted by anyone by permanently curing intractable spinal patients. It is for this reason that we are attempting to combine the theoretical evidence gained by fundamental research and the translation of this research to the clinical side. Then, in the near future, we plan on putting every effort into ensuring that clinical research using neural stem cells becomes a reality. In order to achieve a highly safe method of treatment, we wish to strictly conduct our fundamental research and clarify the mechanisms behind regeneration.” These words from Dr. Okano express his research ambitions.


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03.Actively Undertaking Researcher Development and Joint Research

In addition to advancing fundamental research toward the regenerative treatment of the nervous system, Dr. Okano is also concentrating his efforts toward the fostering of the next generation of researchers. In 2003, the “Center for the Integration of Basic and Clinical Research in Stem-Cell Medicine and Immunology − New developments based on human cells and in vivo experimental medicine” was adopted by the “21st-Century COE Program” of the Ministry of Education, Culture, Sports, Science and Technology. Over five years, considerable research results of the world’s highest standards were achieved in stem cell biology, regenerative medicine, immunology and autoimmune disease research.

Although he says “the world of regenerative medicine is a harsh and competitive world for researchers globally,” Dr. Okano also sends a passionate message that “this is new ground that no one has touched, and as a researcher no other work is as enjoyable or as satisfying. I sincerely hope that young scientists with a ‘can do’ attitude can contribute toward this research.”

Furthermore, Dr. Okano is also highly motivated in regards to joint research. He clearly acknowledges, “Other universities and the private sector have achieved a large number of real results in this field. From now onward, we hope to tackle a better system of research through cooperation. ”Dr. Okano stands at the forefront of regenerative medicine of the nervous system in the world. His stance holds the key to the possibility of fundamentally altering medical treatments.

“This is a field that really stimulates your intellectual curiosity as a researcher, so I’m expecting great things from young scientists.” − Dr. Hideyuki Okano


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04.A Laboratory Filled with the World’s Most Prestigious Researchers and Equipment

Currently, Dr. Okano’s laboratory consists of 5 Research Groups and 2 independent (professorial) chairs. With a team of researchers, engineers, secretaries and other staff of 70 strong, this laboratory can be considered world class. In addition to the laboratories that house the common marmosets, mice or drosophila flies, this research facility stands at the forefront, and is equipped with the latest observation and measurement devices, including Confocal Microscopes and Cell Sorters. Of the numerous microscopes being used, the latest to be introduced into the laboratory is the KEYENCE BZ-X Series Fluorescence Microscope. Amongst the laboratory researchers, it was said that the assessment of this device was positive during demonstration, even before the device was purchased. One example application for this microscope is the observation of stem cells in relation to spinal damage. This device allows the observation of the entire spinal cord at low magnification.

Additionally, the Image Stitching function allows for an even larger field-of-view by merging several magnified images into a single, wide-field image, reducing the amount of time needed to conduct research. By using this function, wide-range images with even brightness can be created in a short period of time by automatically associating multiple images.

A laboratory scene displaying the line-up of state-of-the-art observation and measurement devices.

Dr. Okano expresses the results of introducing the BZ-X Series Series into the laboratory workplace: “Up until now, image synthesis was a troublesome task, taking up much of the researchers valuable time. However, by using the BZ-X Series Series, an experiment that once took 2 weeks will now only take us 3 days. With this type of increased efficiency, we can repeat the same experiment many times, increasing the throughput. Through this, we are able to confirm the reproducibility of the experiments that are the backbone of accuracy. This is a particularly important component of fundamental research, and a great advantage for any scientist in the pursuit of the truth.”


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05.The BZ-X Series – Essential in the Observation of the Overall Image of the Spinal Cord

Despite only just being introduced into the laboratory, over 20 researchers have already begun utilizing the BZ-X Series Microscope. This is because the user-friendliness of the various functions links directly with the improvement of research efficiency.

Dr. Okano evaluates the BZ-X Series: “Simply by conducting research in an unknown field such as this, it becomes of utmost importance to strictly prove whether or not results are showing that nerve cells really are regenerating, or whether the results are a singular phenomenon. For this reason, it is essential we first use the BZ-X Series to confirm the entire image of things such as the spinal cord.”

In one of the world’s leading laboratories, the introduction of a large number of state-of-the-art observation devices is not surprising. Amongst all of these devices, according to Dr. Okano, the “BZ-X Series was essential.” “There are various microscope devices for high-magnification or high-resolution uses made from different manufacturers; however, the conclusion was made that in situations where the entire cell needed to be observed, there was only the BZ-X Series.” When deciding on the purpose of this purchase, the general versatility of the device within the laboratory had to be taken into consideration. “The decision to purchase was made after taking into consideration the device’s ability to benefit all research staff and not be limited to a single use.”

The BZ-X Series positioned within the Laboratory. One advantage lies in its compact size.

In terms of general versatility, the ease in which any person could use the device was also considered. From this standpoint, the BZ-X Series differs from confocal microscopes in that a high level of skill to use the device is not required, nor does it require a specialist engineer to work with the device. Even a first-time user can become quickly proficient in operating the microscope, adding to the appeal of benefiting the overall research.

In addition to the improvement of research efficiency, Dr. Okano also points out another key feature: image quality. “A clean and clear magnified image can make the difference between a pass or fail of a thesis being reviewed,” he says. From this perspective, the BZ-X Series leaves nothing left to be desired.


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06.Functions Unique to the BZ-X Series Contribute to the Improvement of Research Efficiency

We asked the opinion of a researcher actually using the BZ-X Series in the laboratory. Dr. Takehiko Sunabori (Assistant Professor, School of Medicine, Keio University), is currently studying the differentiation mechanisms of neural stem cells of the cerebral cortex. He takes a sample by slicing a cross section of the cerebral cortex of a common marmoset. He then uses the BZ-X Series to capture over time the process of neuron production from neural stem cells.

Dr. Takehiko Sunabori, Assistant Professor, School of Medicine, Keio University.

Dr. Sunabori uses the BZ-X Series together with the confocal microscope when observing the samples, and he states that “to observe the entire sample at low magnification, or to correct the focus of a blurred image, the BZ-X Series is extremely beneficial.” He goes on to say that he occasionally uses the “Image Stitching” function that corrects for any connecting links or brightness differences when stitching magnified images.

“Up until now, we have been manually stitching each individual image. This takes time and there was always uneven contrast, leading to a problem with image quality. This task is now automatically conducted by the BZ-X Series, and all of our previous issues have been resolved all at once. Whereas previously it could take several hours to correct and combine a series of 6 photographs of the cerebral cortex, now it only takes a few minutes. I am deeply satisfied at the ability to acquire high quality images.”

According to Dr. Sunabori, in recent years, we are in “an age where good quality is taken for granted” when referring to photographs published within a thesis. Dr. Sunabori says that he himself always pays careful attention to image quality when taking photos.


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07.The BZ-X Series starts up quickly after power-up enabling immediate observation

The function that is truly appreciated by Dr. Sunabori when observing the entire image of a sample, is the Quick Full Focus function. The focal position of the objective lens is moved electrically along the Z-axis, and images are captured at different focal points throughout the sample, producing a fully-focused image in the end. In situations where the depth of field differs, such as the axons of the central nervous system, by using this function the cumbersome task of adjusting the focus is avoided.

Furthermore, the function assisting in the measurement of the number of cells within a sample is the “Dynamic Cell Count” function. This function does not use binary outline extraction, but rather adopts an original extraction method that separates individual entities of differing brightness. Even cells that are not circular but rather conglutinate, can still be separated and counted, increasing the accuracy of the cell count. Alongside being a beneficial function to research, a feature that is strongly popular among researchers is the quick start-up of the device. “Previously, to calibrate the optimal settings of a fluorescent microscope took both time and patience. That is why the BZ-X Series is great, as observations can be made as soon as you wish to make them. The device is also popular among post-graduate students who frequently use such devices.”

Stained image of ependyma cells of an adult mouse. The image to the left is the raw data of 5 images across and 8 images vertically captured and connected together. The points of connection stand out as the contrast differs. The image on the right, in comparison, is an image produced by using the BZ-X Series Image Stitching function, where the connection contrasts between the different images have been automatically corrected. These connections no longer stand out. From capturing the image to combining the images and correcting them takes under 3 minutes using the BZ-X Series. (Photographs provided by: Dr. Takehiko Sunabori, Assistant Professor, School of Medicine, Keio University)

Dr. Okano’s research facility stands at the global forefront of regenerative treatment research of the nervous system. In order to remain at the forefront, however, this research facility must push through the rigorous international competition it faces. As research constantly advances, one of the greatest challenges is how to increase the efficiency of the observation of experiment samples. The BZ-X Series, with its beneficial functions and user-friendliness, is strongly supporting the groundbreaking research conducted by the Okano Research Institute.

(Current to July, 2008)


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< Did You Know? > Neural Stem Cells

Neural stem cells are stem cells that produce the neurons and glial cells the make up the nervous system. Conventionally, the common perception within the medical field was that adult mammalian brains did not produce neural cells. According to Dr. Okano’s research, however, it has been clarified that neural stem cells exist within the brain. This has led to a door opening on the path toward the regenerative treatments of the central nervous system.

< Did You Know? > iPS Cells

iPS stands for “induced pluripotent stem cells.” These are pluripotent stem cells that are created from somatic cells. Theoretically, any cell composition within the body can be created from iPS cells. However, research is still in the very early stages, with many questions still to be answered, such as the tumorigenic transformation of cells during differentiation.


Dr. Hideyuki Okano

Professor, Department of Physiology, School of Medicine, Keio University Doctor of Medicine

Born 1959. Graduated School of Medicine, Keio University in 1983. Beginning as an Assistant to the Department of Physiology, School of Medicine within the same university; he became an Assistant to the Institute for Protein Research, Osaka University; Assistant to the Chemical Laboratory, Institute of Medical Science, The University of Tokyo; Professor of Molecular Neurobiology of Institute of Basic Medical Sciences, University of Tsukuba; Professor of Neural Function Anatomical Science Research Division of the School of Medicine, Osaka University. He then came to his current post at Keio University in 2001. Between 2003 and 2008, he led the stronghold of the "Center for the Integra - tion of Basic and Clinical Research in Stem-Cell Medicine and Immunology" of the “21st-Century COE Program.” His main research fields include: molecular neurobiology, developmental biology and regenerative medicine. Over the years he has been awarded many honors, including the “Medical Award of The Japan Medical Association”; “Distinguished Scientists Award”; “The Commen - dation by the Minister of Education, Culture, Sports, Science and Technology (Prizes for Science and Technology)”; “Stem Cells Lead Reviewer Award”; and the “Inoue Prize for Science.”

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