Generation of Engraftable Hematopoietic Stem Cells From Induced
Pluripotent Stem Cells by Way of Teratoma Formation

Hematopoietic stem cell (HSC) transplantation in the form of bone marrow or cord blood transplantation is now a standard treatment for leukemia and immunodeficiency diseases. However, stringent requirement of HLA-matching for transplantation has been an obstacle to HSC transplantation. Development of induced pluripotent stem cell (iPSC) technology has enabled generation of patient-specific PSCs, opening a route to cell therapy using a patient’s own cells. Generation of HSCs from patient-derived PSCs has thus become a major goal of regenerative medicine, but generation of truly functional HSCs, HSCs that can be transplanted into an adult host, from iPSCs has been difficult thus far. In this paper, we demonstrate a unique in vivo differentiation system yielding engraftable HSCs from mouse and human iPSCs in animals carrying teratomas in combination with a maneuver facilitating hematopoiesis. HSCs derived from iPSCs migrated from teratomas into BM of teratoma-bearing mice, and transfer of these HSCs into irradiated recipients showed multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. We applied the system to an immunodeficiency disease model and showed that X-SCID mice could be treated by HSCs derived from gene-corrected clonal iPSCs. Neither leukemia nor tumor was observed in recipients after transplantation of iPSC-derived HSCs. The system that we describe provides opportunities not only to study the biology of hematopoiesis but also to use iPSCs for the treatment of hematologic and immunologic diseases.