Objective: To examine the efficacy of midbrain dopaminergic progenitors derived from human iPS cells, as the cell source for Parkinson’s disease model mouse, by analyzing distribution of differentiated cells and evaluating improvement of motor function in host animals.

Background: It has been reported that the fetal cell transplantation could improve motor symptoms of Parkinson’s disease patients. However, it is not used as a general treatment due to dyskinesia or ethical problems. Recently, midbrain dopaminergic progenitors derived from human iPS cells are expected as a potential cell source for future regenerative medicine because they are effective for rodent and primate PD models. In this study, we differentiated human iPS cells into highly-enriched dopaminergic neural progenitor cells without cell sorting used in previous studies and transplanted these cells into PD model mice, to evaluate safety and effectiveness of these cells as a source of regenerative medicine.

Methods: To establish unilateral Parkinson model mice, we injected 6-OHDA into the striatum of immunodeficiency model mice. Severity of model mice were evaluated by rotation behavior of them after subcutaneous injection of apomorphine. Human iPS cells from healthy subjects are differentiated into dopamine neural progenitor cells by using a neural differentiation protocol we recently established. After the transplantation, we continuously evaluated the apomorphine-induced rotation behavior of recipient. Four months after transplantation, we sacrificed the animals and analyzed their brain section to evaluate differentiation properties of transplanted cells in that.

Results: We established 19 6-OHDA injected PD model mice that met the criteria of PD symptoms. Then dopaminergic progenitors were transplanted into 12 of them and saline was injected into 7 of them as a sham group. No tumor formation was observed in the brain section at four months after transplantation. At three months after transplantation, the transplant group began to recover from apomorphine-induced abnormal rotation behavior while the sham group did not.

Conclusions: Highly-enriched dopaminergic neural progenitor cells differentiated from human iPS cells by our neural induction protocol could be transplanted safely even without purification by cell sorting. Further transplantation and investigation are ongoing to confirm statistical significance of improved motor function in host animals.

References: Fujimori K, Matsumoto T, Kisa F, Hattori N, Okano H, Akamatsu W. (2017). Escape from Pluripotency via Inhibition of TGF-β/BMP and Activation of Wnt Signaling Accelerates Differentiation and Aging in hPSC Progeny Cells. Stem Cell Reports 9, 1675-1691. Bumpei Samata, Daisuke Doi, Kaneyasu Nishimura, Tetsuhiro Kikuchi, Akira Watanabe, Yoshimasa Sakamoto, Jungo Kakuta, Yuichi Ono & Jun Takahashi. (2016). Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun 7, 13097.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/transplantation-therapy-of-human-ips-cell-derived-dopamine-neural-progenitor-cells-for-parkinsons-disease/