October 14, 2016
Japan researchers enhance the purity of cells for Parkinson's disease therapy
Parkinson's disease is a neurodegenerative disorder that causes a debilitating loss of midbrain dopaminergic (mDA) neurons. Much evidence supports stem cell therapies as remedies for this degenerative effect. Research is still needed, however, to identify which neural subpopulations derived from the stem cells leads to best outcomes. A new study by researchers at CiRA shows that LRTM1, a protein that may contribute to synapse formation and axon guidance, could be an invaluable marker of the ideal cells. The report can be seen in Nature Communications.
It is anticipated that CiRA Professor Jun Takahashi and his lab will lead the first iPS cell-based therapy for Parkinson's disease patients. "We have reported other markers for [mDA] neurons. Because we plan the first patient trials, we want to make the population as pure as possible," said Takahashi. By preparing neurons from stem cells and then selecting those that expressed LRTM1, the scientists could increase the number of transplanted cells that survived in rats and also improve Parkinsonian symptoms.
The discovery of LRTM1 was based on gene studies. Based on its previous work, the group already knew which genes indicated stem cells that were likely to differentiate into mDA neurons. Further analysis revealed that five genes coded for proteins on the cell surface, but "LRTM1 was the only protein exclusively expressed in the brain region that produces [mDA] neurons," said Takahashi. Important was that these cells did not express genes consistent with a tendency to proliferate, which suggests they are not susceptible to growing tumors, a risk that must be considered in all stem cell-based therapies. Instead, when transplanted into rat and monkey brains, the cells developed into mature mDA neurons and extended more neuronal fibers to the host brain than did the transplant of populations that did not express LRTM1. "All our data indicated cells expressing LRTM1 give better results."
LRTM1 adds another marker to the list of indicators Takahashi's team is using to prepare mDA neurons from stem cells. Each stem cell has the potential to differentiate into all neuron types in the brain, but the specific loss of mDA neurons means only a very select group of cells should be used in the therapy. Based on these findings, Takahashi is optimistic the list of markers will soon be sufficient for patient treatment. "We hope to start our first patient trials in the next two to three years."
Journal: Nature Communications
Title: "Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1"
Authors: Bumpei Samata1, Daisuke Doi1, Kaneyasu Nishimura1, Tetsuhiro Kikuchi1, Akira Watanabe1, Yoshimasa Sakamoto2, Jungo Kakuta2, Yuichi Ono2, and Jun Takahashi1,3
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- KAN Research Institute Inc, Kobe, Japan
- Department of Neurosurgery, Kyoto University School of Medicine, Kyoto, Japan