Year 3

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and retain the ability to differentiate into all
cell types in the body. Therefore, as a renewable source of numerous cell types, pluripotent stem cells hold great promise for
human cell replacement therapy. Significant progress has been made in establishing the conditions to differentiate
hESCs into several lineages of biologically active cells. For example, recent studies in in vivo models have shown that
myocytes differentiated from hESCs improve cardiac function after myocardial infarction, and oligodendroglial
progenitors could rescue spinal cord injury. hESC-derived lung epithelium has been shown to repair and improve the
lung function after acute lung injury. In addition, pancreatic β cells derived from hESCs are functional in in vivo
models. These recent encouraging reports suggest that hESC-based cell replacement therapies can be achieved in the
near future. Despite the promising progress in generating hESC-derived tissues, several major obstacles must be
addressed prior to successful application of hESC-based cell replacement therapies in patients. One major
complication is the immune-mediated rejection of hESC-derived cells by the recipient due to expression of
allo-antigens and specific alterations in gene expression. We are working to “turn off” the cells of the immune system
responsible for graft rejection but only in the response to grafted tissues derived from stem cells. This strategy is a
significant improvement over total immune suppression which is typically used to promote graft acceptance. This
year we have made significant progress in that we have generated stem cells that are accepted as grafts and begun to
dissect the molecular pathways responsible for graft acceptance.