Xenogeneic in Utero Transplantation For Generation of Animals Producing Human Blood Cells

Yutaka Hanazono, MD, PhD

Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University

A major barrier for most tissue or cellular transplantation therapies is the shortage of donors.  That is also the case with the supply of red blood cells, platelets and hematopoietic stem cells.  Our study aims to produce human blood cells from induced pluripotent stem (iPS) cells in vivo in animals.  Human iPS cells have remarkable abilities to proliferate indefinitely and differentiate into multiple tissue and blood cells.  In addition, iPS cells can be generated from adult skin or peripheral blood cells without complicated ethical issues.  Therefore, directed differentiation of human iPS cells into functionally defied human blood cells is a goal in providing an inexhaustible and potentially customized supply of the cells.  Clearly directed differentiation of human iPS cells is still in its infancy and the methodology is quite limited.  Many researchers have studied in vitro specific differentiation programs through manipulation of the cytokine milieu, cellular microenvironment, and conditional activation of specific gene expression.  Despite these efforts, neither hematopoietic stem cells nor red blood cells nor platelets can be efficiently produced from iPS cells in vitro.  Another strategy to produce human blood cells from iPS cells would be the utilization of in vivo local microenvironment or niche in animals.  In this context, we are conducting sheep in utero transplantation (IUT) of human hematopoietic stem or precursor cells to generate animals producing human blood cells.  Large animals would be able to produce a large number of human blood cells taking advantage of their sizes compared to rodents.  Among large animals, sheep have some advantages; relative ease of handling and low abortion rates after IUT.  Pigs are also good candidates.  I will review our previous studies and show some of preliminary results.