Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury

Kota Kojima; Hiroyuki Miyoshi; Narihito Nagoshi; Jun Kohyama; Go Itakura; Soya Kawabata; Masahiro Ozaki; Tsuyoshi Iida; Keiko Sugai; Shuhei Ito; Ryuji Fukuzawa; Kaori Yasutake; Francois Renault-Mihara; Shinsuke Shibata; Morio Matsumoto; Masaya Nakamura; Hideyuki Okano

doi:10.1002/sctm.18-0096

Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury

Stem Cells Transl Med. 2019 Mar;8(3):260-270. doi: 10.1002/sctm.18-0096. Epub 2018 Nov 28.

Authors

Kota Kojima^{1

2}, Hiroyuki Miyoshi¹, Narihito Nagoshi², Jun Kohyama¹, Go Itakura^{1

2}, Soya Kawabata^{1

2}, Masahiro Ozaki^{1

2}, Tsuyoshi Iida^{1

2}, Keiko Sugai^{1

2}, Shuhei Ito^{1

2}, Ryuji Fukuzawa³, Kaori Yasutake², Francois Renault-Mihara¹, Shinsuke Shibata¹, Morio Matsumoto², Masaya Nakamura², Hideyuki Okano¹

Affiliations

¹ Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
² Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
³ Department of Pathology, International University of Health and Welfare, Chiba, Japan.

Abstract

Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.

Keywords: Herpes simplex virus thymidine kinase; Human induced pluripotent stem cell-derived neural stem/progenitor cell; Spinal cord injury; Stem cell therapy; Suicide gene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / pathology*
Cell Differentiation / physiology
Cells, Cultured
Disease Models, Animal
Female
Humans
Induced Pluripotent Stem Cells / cytology*
Mice
Mice, Inbred NOD
Mice, SCID
Neural Stem Cells / cytology*
Neurons / physiology
Recovery of Function / physiology
Spinal Cord / physiology*
Spinal Cord Injuries / therapy*
Stem Cell Transplantation / methods