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March 01, 2023

Selective removal of undifferentiated iPS cells from mesenchymal stem cells

The research group led by CiRA Associate Professor Makoto Ikeya has established a method to selectively remove iPS cells from iPS cell-derived mesenchymal stem cells (iMSCs) and purify iMSCs by using brequinar (BRQ), a dihydroorotate dehydrogenase (DHODH) inhibitor.

Mesenchymal stem cells (MSCs) are present in all tissues and are known to directly or indirectly promote tissue regeneration. There are several challenges in acquiring MSCs from living organisms for cell replacement therapies, such as invasiveness, proliferation limitations, and variability in biological properties between different samples. To avoid these issues, MSC production from iPS cells (iMSCs) represents a non-invasive, robust, and highly reproducible alternative. However, there is a risk of teratoma formation from residual undifferentiated iPS cells when using iMSCs for transplantation therapy. Therefore, a method to remove such unwanted iPS cells before transplantation is crucial for realizing safe iMSC-based cell therapy.

This study builds upon previous research that demonstrated that mouse ES/iPS cells could be selectively eliminated by DHODH inhibitors. However, it was unclear whether this approach could be applied to human cells. This study showed that BRQ treatment selectively removes undifferentiated human iPS cells from iMSCs by activating cell cycle arrest and apoptosis. The treatment also triggered transcriptional changes and hindered the growth of 3-dimensional hiPSC aggregates. On the other hand, iMSCs were unaffected by the treatment and maintained their properties and differentiation potentials.

The iMSCs created by the research team are produced by a two-step induction method via an intermediate cell type called neural crest cells. Since the process involves extracting neural crest cells and removing undifferentiated cells using a cell sorter, there is little risk of teratoma formation for small-scale studies. However, many more cells may be transplanted for human clinical applications compared to experiments using small animals such as mice, thus increasing the risk of tumorigenesis proportionately.

The findings from this study are expected to contribute to establishing an additional level of safety for using iMSCs in the future for cell therapy and providing patients undergoing iMSC-based treatments with extra peace of mind.

The results of this study were published online in Frontiers in Cell and Developmental Biology on February 6, 2023.

Paper Details
  • Journal: Frontiers in Cell and Developmental Biology
  • Title: Selective vulnerability of human-induced pluripotent stem cells to dihydroorotate dehydrogenase inhibition during mesenchymal stem/stromal cell purification
  • Authors: Ziadoon Al-Akashi1, Denise Zujur1, Daisuke Kamiya1,2, Tomohisa Kato Jr3, Toru Kondo4 and Makoto Ikeya1,2*
    *: Corresponding authors
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University
    2. Takeda-CiRA Joint Program
    3. Medical Research Institute, Kanazawa Medical University
    4. Institute for Genetic Medicine, Hokkaido University
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