Tissue inhibitor of metalloproteinase proteins inhibit teratoma growth in mice transplanted with pluripotent stem cells

Kyung Ah Choi, Han Kyul Park, Insik Hwang, Hyesun Jeong, Hang Soo Park, Ah Young Jang, Yong Namkung, Donghun Hyun, Seulbee Lee, Byung Min Yoo, Han Jin Kwon, Ki Cheon Seol, Jeong Ok Kim, Sunghoi Hong

Research output: Contribution to journalArticle

Abstract

Pluripotent stem cells (PSCs) can serve as an unlimited cell source for transplantation therapies for treating various devastating diseases, such as cardiovascular diseases, diabetes, and Parkinson's disease. However, PSC transplantation has some associated risks, including teratoma formation from the remaining undifferentiated PSCs. Thus, for successful clinical application, it is essential to ablate the proliferative PSCs before or after transplantation. In this study, neural stem cell-derived conditioned medium (NSC-CM) inhibited the proliferation of PSCs and PSC-derived neural precursor (NP) cells without influencing the potential of PSC-NP cells to differentiate into neurons in vitro and prevented teratoma growth in vivo. Moreover, we found that the NSC-CM remarkably decreased the expression levels of Oct4 and cyclin D1 that Oct4 directly binds to, and increased the cleaved-caspase 3-positive cell death through the DNA damage response in PSCs and PSC-NPs. Interestingly, we found that NSCs distinctly secreted the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 proteins. These proteins suppressed not only the proliferation of PSCs in cell culture but also teratoma growth in mice transplanted with PSCs through inhibition of matrix metalloproteinase (MMP)-2 and MMP-9 activity. Taken together, these results suggest that the TIMP proteins may improve the efficacy and safety of the PSC-based transplantation therapy.

Original languageEnglish
JournalStem Cells
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Keywords

  • neural stem cell-derived conditioned medium (NSC-CM)
  • pluripotent stem cells (PSCs)
  • teratoma
  • tissue inhibitor of metalloproteinase (TIMP)
  • transplantation therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Choi, K. A., Park, H. K., Hwang, I., Jeong, H., Park, H. S., Jang, A. Y., Namkung, Y., Hyun, D., Lee, S., Yoo, B. M., Kwon, H. J., Seol, K. C., Kim, J. O., & Hong, S. (Accepted/In press). Tissue inhibitor of metalloproteinase proteins inhibit teratoma growth in mice transplanted with pluripotent stem cells. Stem Cells. https://doi.org/10.1002/stem.3132