Neuronal Regeneration

kaoJun Takahashi, MD, PhD, Professor  btn

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 Education

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease (PD). Towards clinical application of iPSCs, we have developed a method for 1) scalable DA neuron induction on human laminin fragment and 2) sorting DA progenitor cells using a floor plate marker, CORIN. The grafted CORIN+ cells survived well and functioned as midbrain DA neurons in the 6-OHDA-lesioned rats, and showed minimal risk of tumor formation. In addition, we performed a preclinical study using primate PD models. Regarding efficacy, human iPSC-derived DA progenitor cells survived and functioned as midbrain DA neurons in MPTP-treated monkeys. Regarding safety, cells sorted by CORIN did not form any tumors in the brains for at least two years. Finally, MRI and PET imaging was useful to monitor the survival, expansion and function of the grafted cells. Based on these results, we have started a clinical trial to treat PD patients at Kyoto University Hospital in Kyoto, Japan in 2018.

r-115-1

human iPSC-derived DA neurons

高橋淳研究室図

A protocol for clinical application of human iPSC-derived DA neurons


Recent Publications

  1. Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, Mawatari A, Glasser M F, Shiina T, Ishigaki H, Itoh Y, Okita K, Yamasaki E, Doi D, Onoe H, Ogasawara K, Yamanaka S, Takahashi J. MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun. 8:385 (2017)
  2. Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, Mizuma H, Takara S, Takahashi R, Inoue H, Morita S, Yamamoto M, Okita K, Nakagawa M, Parmar M, Takahashi J. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548: 592-96 (2017)
  3. 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)
  4. 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)
  5. 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)

Neuronal Regeneration

Professor:Jun Takahashi
Senior Assistant Professor:Asuka Morizane
Assistant Professor:Daisuke Doi
Assistant Professor:Tetsuhiro Kikuchi
Tel: +81-75-366-7052
Fax: +81-75-366-7071
e-mail:jbtaka@cira.kyoto-u.ac.jp
URL:http://www.cira.kyoto-u.ac.jp/jtakahashi/