Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1

• Published in: Nature communications Vol. 7; no. 1; p. 13097
• Main Authors: Samata, Bumpei, Doi, Daisuke, Nishimura, Kaneyasu, Kikuchi, Tetsuhiro, Watanabe, Akira, Sakamoto, Yoshimasa, Kakuta, Jungo, Ono, Yuichi, Takahashi, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.10.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 631/378/1689; 631/532/2064; 631/532/2182; 692/308/2171; Animals; Antibodies; Brain research; Cell Differentiation - genetics; Cell Separation - methods; Cells, Cultured; Dopaminergic Neurons - cytology; Dopaminergic Neurons - metabolism; Female; Gene expression; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Macaca fascicularis; Male; Mesencephalon - cytology; Mesencephalon - metabolism; Mice, Inbred C57BL; multidisciplinary; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - therapy; Parkinson's disease; Proteins - genetics; Proteins - metabolism; Rats, Sprague-Dawley; Research centers; Science; Science (multidisciplinary); Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Stem Cell Transplantation - methods; Stem cells; Transcription factors; Transplantation, Heterologous; Japan
• DOI: 10.1038/ncomms13097
• ISSN: 2041-1723

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 + cells survive and differentiate into mDA neurons in vivo , resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 + cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients. Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.