'Japanese Society for Biological Sciences in Space'
Abstract
Due to current shortages of available donor tissues and organs, researchers have turned to human pluripotent stem cells (hPSCs) as a potential resource for cell replacement therapy. hPSCs offer many advantages including their inherent ability to self-renew along with the capacity to generate any cell type of the human body. Tremendous progress has been made in the development of strategies to differentiate these cells into clinically useful cell types, such as neurons and cell types of the cardiovascular system. As with any transplanted cells and tissues, potential risk of an immune response against donor cells through T cell recognition of mismatched Major Histocompatibility Complex (MHC) must be considered. Unfortunately, existing banks of human embryonic stem cells (hESC) are limited in available MHC diversity and there are many ethical and financial hurdles hindering the creation of new hESC lines. In an effort to generate hPSC lines with more genetic diversity, the Loring lab at The Scripps Research Institute has made use of induced pluripotent stem cell (iPSC) technology to generate a bank of ethnically diverse cells. In this study I used two hiPSC lines from this bank along with a commercially available hESC line to investigate changes in the immunogenicity of hPSCs as they are differentiated in vitro. Given the importance of MHC in immune rejection, I first examined MHC expression in these hPSCs and their derivatives. I found that, in their undifferentiated state, neither hiPSCs nor hESCs express detectable levels of MHC molecules. However, when these cells are differentiated in vitro, MHC expression levels increase. While MHC expression levels were significantly higher in the iPSC-derived differentiated cells than the undifferentiated cells, they were still much lower than levels seen in primary cells derived from adult tissue. In addition, immune responses against differentiated derivatives were measured in vitro using human peripheral blood mononuclear cells (PBMCs) in a mixed lymphocyte reaction (MLR). There was significant proliferation in the allogenic MLR with no statistically significant difference between the primary allogenic cells or the allogenic hPSC derivatives. The autologous cells only generated a minimal immune response and there was no statistically significant difference between the primary autologous cells and the autologous hPSC derivatives. These data support the importance of MHC matching of hPSC-derived tissues for cellular therapy. It also further supports the utility of genetically diverse hPSC banks, particularly ones that strive to encompass the majority of possible immunologic backgrounds. Together with advances in cellular differentiation and tissue engineering, researchers may be able to use iPSC-based technology to address the current shortage of immunologically compatible donor organs
