Tumorigenicity studies for human pluripotent stem cell-derived products.

Human pluripotent stem cells (hPSCs), i.e. human embryonic stem cells and human induced pluripotent stem cells, are able to self-renew and differentiate into multiple cell types. Because of these abilities, numerous attempts have been made to utilize hPSCs in regenerative medicine/cell therapy. hPSCs are, however, also tumorigenic, that is, they can give rise to the progressive growth of tumor nodules in immunologically unresponsive animals. Therefore, assessing and managing the tumorigenicity of all final products is essential in order to prevent ectopic tissue formation, tumor development, and/or malignant transformation elicited by residual pluripotent stem cells after implantation. No detailed guideline for the tumorigenicity testing of hPSC-derived products has yet been issued for regenerative medicine/cell therapy, despite the urgent necessity. Here, we describe the current situations and issues related to the tumorigenicity testing of hPSC-derived products and we review the advantages and disadvantages of several types of tumorigenicity-associated tests. We also refer to important considerations in the execution and design of specific studies to monitor the tumorigenicity of hPSC-derived products.

[1]  S. Nishikawa,et al.  Highly Sensitive In Vitro Methods for Detection of Residual Undifferentiated Cells in Retinal Pigment Epithelial Cells Derived from Human iPS Cells , 2012, PloS one.

[2]  S. Schwartz,et al.  Embryonic stem cell trials for macular degeneration: a preliminary report , 2012, The Lancet.

[3]  D. Prockop.  Defining the probability that a cell therapy will produce a malignancy. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  F. Müller,et al.  A call to standardize teratoma assays used to define human pluripotent cell lines. , 2010, Cell stem cell.

[5]  T. Putti,et al.  Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. , 2009, Stem cell research.

[6]  K. Machida,et al.  Higher susceptibility of NOG mice to xenotransplanted tumors. , 2009, The Journal of toxicological sciences.

[7]  Mark Shackleton,et al.  Efficient tumour formation by single human melanoma cells , 2008 .

[8]  S. Nishikawa,et al.  A ROCK inhibitor permits survival of dissociated human embryonic stem cells , 2007, Nature Biotechnology.

[9]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice , 2005 .

[10]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. , 2005, Blood.

[11]  Mamoru Ito,et al.  NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. , 2002, Blood.

[12]  B. Stockinger,et al.  Following the development of a CD4 T cell response in vivo: from activation to memory formation. , 1999, Immunity.

[13]  A. Hamburger,et al.  Primary bioassay of human tumor stem cells. , 1977, Science.