Jun Takahashi, MD, PhD, Professor
We are developing a cell replacement therapy for the neurological disorders by using stem cells, especially embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The main target is Parkinson’s disease, and our research focuses on induction of dopaminergic (DA) neurons from these cells and transplantation of the cells into the brain to improve neurological symptoms.
Research and EducationIn 2012, we have reported the results of transplantation of human ESC-derived neural progenitor cells (NPCs) into primate models Parkinson’s disease. We have herein, for the first time, compared the growth and function of human ESC-derived cells with different stages of neural differentiation implanted in the brains of primate models of Parkinson’s disease. We showed that residual undifferentiated cells expressing ESC markers present in the cell preparation can induce tumor formation in the monkey brain. In contrast, a cell preparation matured by 42-day-culture with BDNF/GDNF treatment did not form tumors, and survived as primarily dopaminergic neurons. In addition, the monkeys with such grafts showed behavioral improvement for at least 12 months. These results support the idea that human ESCs, if appropriately matured, can serve as a source for dopaminergic neurons without forming any tumors in a primate brain. Now, we are inducing DA neurons from human iPSCs, and developing a safe and efficient method for clinical application of the cells.
human iPSC-derived DA neurons
A protocol for clinical application of human iPSC-derived DA neurons
- Samata B, Doi D, Nishimura K, Kikuchi T, Watanabe A, Sakamoto Y, Kakuta J, Ono Y, Takahashi J. Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun. 7:13097 (2016)
- Nishimura K, Doi D, Samata B, Murayama S, Tahara T, Onoe H, Takahashi J. Estradiol facilitates functional integration of induced pluripotent stem cell-derived dopaminergic neurons into striatal neuronal circuits via activation of integrin α5β1. Stem Cell Reports. 6(4): 511-524 (2016)
- Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, Sekiguchi K, Nakagawa M, Parmar M, Takahashi J. Isolation of Human Induced Pluripotent Stem Cell-derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation. Stem Cell Reports. 2(3): 337-350 (2014)
- Morizane A, Doi D, Kikuchi T, Okita K, Hotta A, Kawasaki T, Hayashi T, Onoe H, Shiina T, Yamanaka S, Takahashi J. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a nonhuman primate. Stem Cell Reports 1(4): 283-292 (2013)
- Doi D, Morizane A, Kikuchi T, Onoe H, Hayashi T, Kawasaki T, Motono M, Sasai Y, Saiki H, Gomi M, Yoshikawa T, Hayashi H, Shinoyama M, Mohamed R, Suemori H, Miyamoto S, Takahashi J. Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson’s disease. Stem Cells 30(5): 935-945 (2012)
Neuronal RegeneationProfessor：Jun Takahashi
Assistant Professor：Asuka Morizane
Assistant Professor：Daisuke Doi