Human Stem Cell Differentiation In Vivo in Large Animals

Abstract

The discovery of common placental circulation between twins coupled with the development of erythrocyte profiling in cattle allowed Ray Owen (Science 1945) to determine that dizygotic twins were chimeric with their sibling’s blood cells after birth. Thus, the author concluded that self-tolerance is acquired during fetal development through the intermingling of sibling cells via the placental circulation and, as a corollary, immune tolerance to self is not genetically determined or innate. Pixley’s group has also exploited this process to engraft human stem cells in a large animal (sheep) via in utero transplantation (IUT). Advantages to large animal investigation include long life span, large size, and serial sampling. Using parallel studies in developing sheep fetuses, stem cell engraftment receptivity and sheep lymphoid ontogeny were assayed longitudinally. They were able to identify an engraftment window and propose their antigen exposure model to explain acquisition of immune tolerance to self as chimeric animals display lifelong immune tolerance to the graft. The subsequent chimeras yield human hematopoietic, islet, hepatic, cardiac, and gastrointestinal cellular elements in situ. Circulating human proteins (IgM, albumin, factor VIII, C-peptide, and alpha-fetoprotein) are detected years after transplantation. Therefore, a fully tolerant large animal host provides an ideal method to test human stem cell differentiation in vivo. This chapter will discuss evidence for immune tolerance and potential advantages of IUT in assaying stem cell differentiation in vivo (in comparison to immunodeficient animal models). Limitations to stem cell differentiation following IUT will be discussed as well.KeywordsFetal toleranceIn utero transplantationSelf/non-self discriminationPluripotencyStem cell