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 patientís 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.
The Exploratory Research for Advanced Technology (ERATO),
NAKAUCHI Stem Cell and Organ Regeneration Project
Title: Generation of Engraftable Hematopoietic Stem Cells From Induced Pluripotent Stem Cells by Way of Teratoma Formation
Authors: Nao Suzuki, Satoshi Yamazaki, Tomoyuki Yamaguchi, Motohito Okabe, Hideki Masaki, Satoshi Takaki, Makoto Otsu and Hiromitsu Nakauchi
Hiromitsu Nakauchi M.D.,Ph.D.
Professor and Director, Center for Stem Cell Biology and Medicine,
The Institute of Medical Science, The University of Tokyo
Department of Research Project
Japan Science and Technology Agency (JST)