Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation

PLoS One. 2015 Feb 23;10(2):e0116413. doi: 10.1371/journal.pone.0116413. eCollection 2015.

Abstract

Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / drug effects*
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Induced Pluripotent Stem Cells / cytology*
  • Mice
  • Neural Stem Cells / transplantation*
  • Spinal Cord / drug effects*
  • Spinal Cord / immunology
  • Spinal Cord / pathology
  • Stem Cell Transplantation / methods*

Substances

  • Immunosuppressive Agents

Grants and funding

This work was supported by grants from the Japan Science and Technology (JST)-California Institute for Regenerative Medicine (CIRM) collaborative program; a Grant-in-Aid from the Zenkyoren (National Mutual Insurance Federation of Agricultural Cooperatives) Research Foundation; a Grant-in-Aid from the General Insurance Association of Japan to MN; Grants-in-Aid for the Research Center Network for Realization of Regenerative Medicine and the Centers for Clinical Application Research on Specific Disease/Organ from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and the JST; Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS); Keio Gijuku Academic Development Funds; a Grant-in-Aid for the Global Center of Excellence (COE) program from the MEXT to Keio University; and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the MEXT to HO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.