Institute of Biomedical Research and InnovationRegenerative Medicine Research
Outline of Our Research
R&D of novel therapy for regeneration of brain function
It had been believed that neuronal regeneration cannot occur after injury. The major causes of bed-ridden are stroke and dementia, and there is no effective therapy for regeneration of brain function at present.
We have demonstrated that the neuronal regeneration after stroke can be achieved by therapeutic angiogenesis using hematopoietic stem cell (Figure 1). Our clinical trial of autologous hematopoietic stem cell transplantation for stroke patients showed favorable trends in acceleration of functional recovery. Furthermore, we have recently figured out the mechanism of how hematopoietic stem cell activates angiogenesis at ischemic tissue. Based on these findings, R&D projects of novel therapy for stroke and dementia are ongoing.
- Figure 1. Angiogenesis and neurogenesis after stroke
- Endogenous neurogenesis is activated after cerebral infarction but, without angiogenesis, induced neural stem cells mostly die from apoptosis (A). We had revealed that, when the angiogenesis process is activated by the administration of hematopoietic stem cells or other methods, induced neural stem cells survive, mature and function, contributing to improving neural function (B). (Cited and modified from Taguchi et al. J. Clin. Invest. 2004)
- Research content
Development of novel therapy by stem cells transplantation that improves neuronal recovery after stroke
(1) Background to our research
- ・Angiogenesis and neurogenesis: Angiogenesis is known to be essential for neurogenesis in the mammalian embryo and adult songbird. The recovery process from cerebral infarction, similar to the wound healing process, consists of three stages: 1) an inflammatory phase for about two days after stroke; 2) a angiogenesis phase for about two weeks after stroke; and 3) a subsequent maturation phase. The key to promoting neurogenesis is the activation of angiogenesis in the angiogenesis phase (Figure 2).
- ・Therapeutic angiogenesis using hematopoietic stem cells (HSCs): Vascular endothelial growth factor (VEGF) is known to activated angiogenesis. However, VEGF alone cannot induce sufficient angiogenesis at ischemic tissue. In contrast, HSCs had been shown to have the potential that can induce sufficient angiogenesis. In a clinical trial in patients with limb ischemia undergoing autologous hematopoietic stem cell transplantation, we confirmed the significant effect of HSCs in promoting angiogenesis at ischemic limb (Figure 3). In the subsequent clinical trial in patients with severe cerebral infarction undergoing autologous hematopoietic stem cell transplantation, we had shown that the promotion of angiogenesis is highly likely to promote regeneration of brain microcirculation and the improvement of brain metabolism (Figure 4).
- Figure 2. Time course in the regeneration process after cerebral infarction
- The recovery process from stroke, similar to the wound healing process, consists of the inflammatory, angiogenesis and maturation phases (A). We consider that activation in the angiogenesis phase activates the entire recovery process, including the maturation phase (B).
- Figure 3. Autologous hematopoietic stem cell transplantation in a patient with limb ischemia
- An intractable ischemic ulcer was cured by autologous hematopoietic stem cell transplantation (A). The patient’s angiographic findings also improved (B). (Cited and modified from Taguchi et al. Eur. J. Vasc. Endovasc. Surg. 2003)
- Figure 4. Cerebral circulation and metabolism improved by autologous hematopoietic stem cell transplantation in a patient with cerebral infarction
- After autologous hematopoietic stem cell transplantation, an increase in the cerebral blood flow (CBF) (A) and the cerebral metabolic rate of oxygen (CMRO2) (B) was observed. (Cited and modified from Stem Cells Dev. 2015)
(2) Details of our research
- ・Identification of causes of non-response to therapeutic angiogenesis by HSCs transplantation: Therapeutic angiogenesis using hematopoietic stem cells (HSCs) has been evaluated in clinical trials in patients with limb ischemia, cerebral infarction, myocardial infarction and other diseases. In these trials, while a dramatic effect was demonstrated in those responding very well to the therapy, there were also many non-responders. We had conducted a clinical trial in patients with limb ischemia or cerebral infarction undergoing autologous hematopoietic stem cell transplantation and noticed the significant difference in transplanted cells between responder or non-responder. We have therefore been engaged in research and development to the optimization of cells to be transplanted.
- ・Elucidation of the mechanism of regeneration of microvasculature using HSCs: Suggested mechanisms behind angiogenesis using HSCs include the differentiation of HSCs into endothelial cells and the release of different kinds of vascular growth factors from HSCs. Unfortunately, there is no data yet that fully supports these hypotheses. We have found that there is an unexpected mechanism behind therapeutic angiogenesis using HSCs. Based on this finding, we are conducting a study to elucidate the whole picture of its signal transduction pathway as well as developing therapeutics that apply the mechanism of angiogenesis using HSCs.
- ・Development of medical devices to spread regenerative medicine: Separation and purification of stem cells are necessary for revascularization therapy using HSCs. However, cell preparation facilities for manual separation and purification require high costs for construction and maintenance. In addition, cell separation procedures are complicated. Due to these reasons, it is difficult to spread revascularization therapy using HSCs. Because the cause of non-response and the therapeutic mechanism have been identified, it has become possible to purify effective stem cell groups while maintaining the functions of autologous hematopoietic stem cells. We are developing an automatic stem cell separator with these functions (Figure 5).
- Figure 5. Development of an automatic stem cell separator based on the results of reverse-translational research
- We solved questions raised in clinical trials in basic research (reverse-translational research). Based on thus obtained results, we are engaged in research and development toward the clinical trial of an automatic stem cell separator.
Development of novel therapy for dementia by regeneration of cerebral vasculature function in elderly
(1) Background to our research
- ・Potential new therapeutic target for dementia in elderly: Causes of deterioration of the brain function in the elderly include 1) the accumulation of toxic proteins, such as amyloid and tau proteins, in the brain; 2) chronic inflammation in the brain; and 3) cerebrovascular disorders. In many cases, a combination of these causes results in the deterioration of neural function, leading to dementia. We consider that age-related deterioration in cerebrovascular function is the underlying cause of the aforementioned symptoms, and that it is possible to improve brain function through the regeneration of aged cerebral microvascular function (Figure 6).
- Figure 6. Improvement of brain function by regeneration of aged cerebral microvasculature
- Cerebrovascular disorders, the accumulation of amyloid beta and tau proteins, and chronic inflammation cause deterioration of neural function. We consider that the underlying cause of these symptoms is age-related deterioration in cerebrovascular function, and that it is possible to regenerate neural function through the regeneration of cerebrovascular function.
(2)Details of our research
- ・Establishment of a joint research and development system: Despite the short history of research in regenerative medicine, therapeutic methods resulting from totally new ideas have come into practical use one after another. As a joint research and development group to address challenging issues of regeneration of brain function in dementia patients, we launched the ReMDI project: Regenerative Medicine for Dementia Initiative in 2018. The objectives of the Initiative are 1) to change the paradigm from conventional research and development based on a defensive approach of inhibiting neuronal cell death to research and development based on an offensive approach of promoting functional regeneration (Figure 7); 2) to form a free- and broad-minded, fun-loving research group of researchers, companies and organizations that are engaged in promoting functional regeneration of the brain in order to address dementia with regenerative medicine as science; and 3) to control dementia by overcoming technical difficulties and using science to solve problems.
- ・Development of dementia treatment using regenerative medical technology: To use the effect of hematopoietic stem cells (HSCs) in promoting cerebral revascularization in developing dementia treatment, we are conducting research 1) to screen for drugs and foods that may have the effect of promoting revascularization similar to that of HSCs with in vitro assay; 2) to examine age-related change in the effect of promoting the angiogenesis of peripheral leukocyte cells and bone marrow HSCs; and 3) to establish animal models of brain pathologies in the elderly and an evaluation method for them. To develop treatment methods from a new perspective, we need to address various issues. Despite such difficulty, in cooperation with a research group of the ReMDI project: Regenerative Medicine for Dementia Initiative, we are conducting research and development that will lead to the development of therapeutics for dementia.
- Figure 7. Therapeutic strategy under the ReMDI project: Regenerative Medicine for Dementia Initiative
- Until now it has been considered impossible to regenerate neural function. Based on this belief, research and development in developing dementia treatment drugs has only been targeted at the prevention of dementia in healthy individuals and patients with mild dementia. In this approach, clinical trials to verify efficacy require a long period of time and a large number of subjects. Under the ReMDI project: Regenerative Medicine for Dementia Initiative, we are conducting research and development targeting the regeneration of neural function in dementia patients. We consider that, with this approach, it is possible to evaluate efficacy in short-period clinical trials in a small number of subjects.
1. Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products.Houkin K, Shichinohe H, Abe K, Arato T, Dezawa M, Honmou O, Horie N, Katayama Y, Kudo K, Kuroda S, Matsuyama T, Miyai I, Nagata I, Niizuma K, Sakushima K, Sasaki M, Sato N, Sawanobori K, Suda S, Taguchi A, Tominaga T, Yamamoto H, Yamashita T, Yoshimine T; Working Group for Guidelines on Development of Cell-Based Products for the Treatment of Cerebral Infarction. Stroke. 2018; 49(4):e145-e152.
2. Treatment evaluation of acute stroke for using in regenerative cell elements (TREASURE) trial: Rationale and design. Osanai T, Houkin K, Uchiyama S, Minematsu K, Taguchi A, Terasaka S. Int J Stroke. 2018; 13(4):444-448.
3. Cell therapy for adult infarction. Sato Y, Kasahara Y, Taguchi A. Cell therapy for perinatal brain injury (ed. Shintaku. SpringerNature). 2018; 119-130.
4. Mutual effect of cerebral amyloid β and peripheral lymphocytes in cognitively normal older individuals.Yasuno F, Kazui H, Kajimoto K, Ihara M, Morita N, Taguchi A, Yamamoto A, Matsuoka K, Takahashi M, Nakagawara J, Tsuji M, Iida H, Kishimoto T, Nagatsuka K. Int J Geriatr Psychiatry. 2017; 32(12):e93-e99.
5. Transplantation of hematopoietic stem cells: Intra-arterial versus intravenous administration impacts stroke outcomes in a murine model. Kasahara Y, Yamahara K, Soma T, Stern DM, Nakagomi T, Matsuyama T, Taguchi A. Transl Res. 2016; 176:69-80
6. Use of t1-weighted/t2-weighted magnetic resonance ratio to elucidate changes due to amyloid beta accumulation in cognitively normal subjects. Yasuno F, Kazui H, Morita N, Kajimoto K, Ihara M, Taguchi A, Yamamoto A, Matsuoka K, Takahashi M, Nakagawara J, Iida H, Kishimoto T, Nagatsuka K. Neuroimage Clin. 2017;13:209-214
7. Mutual effect of cerebral amyloid beta and peripheral lymphocytes in cognitively normal older individuals. Yasuno F, Kazui H, Kajimoto K, Ihara M, Morita N, Taguchi A, Yamamoto A, Matsuoka K, Takahashi M, Nakagawara J, Tsuji M, Iida H, Kishimoto T, Nagatsuka K. Int J Geriatr Psychiatry. 2017;32(12):e93-e99
8. High amyloid-beta deposition related to depressive symptoms in older individuals with normal cognition: A pilot study. Yasuno F, Kazui H, Morita N, Kajimoto K, Ihara M, Taguchi A, Yamamoto A, Matsuoka K, Kosaka J, Kudo T, Iida H, Kishimoto T, Nagatsuka K. Int J Geriatr Psychiatry. 2016;31:920-928
9. Evaluations of intravenous administration of cd34+ human umbilical cord blood cells in a mouse model of neonatal hypoxic-ischemic encephalopathy. Ohshima M, Taguchi A, Sato Y, Ogawa Y, Saito S, Yamahara K, Ihara M, Harada-Shiba M, Ikeda T, Matsuyama T, Tsuji M. Dev Neurosci. 2016;38:331-341
【Review articles in Japanese】
1. Regenerative medicine for stroke. Taguchi A. The Japanese Journal of Physical Therapy. 2017;51(5):451-456
2. Cell based therapy for stroke patients. Taniguchi A. Journal of Clinical and Experimental Medicine. 2017;260(7):563-567
3. Regenerative medicine for stroke. Taguchi A. Medicina. 2016;53(2):340-342
4. Stroke and biomarkers: New development; Hematopoietic stem cell count in peripheral blood. Taguchi A. Molecular Cerebrovascular Medicine. 2016;15(2):17-21
5. Autologous bone marrow monocyte transplantation for cerebral infarction. Taguchi A. Clinical Neuroscience. 2016;34(11):1261-1262