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EMBRYONIC STEM CELLS |
Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
Key Words. Hematopoiesis • Human embryonic stem cells • Natural killer cells • Transplantation
Correspondence: Dan S. Kaufman, M.D., Ph.D., Stem Cell Institute, Translational Research Facility, 2001 6th St. SE, Mail Code 2873, Minneapolis, Minnesota 55455, USA. Telephone: 612-624-0922; Fax: 612-624-2436; e-mail: kaufm020{at}umn.edu
Received on July 27, 2005;
accepted for publication on January 22, 2006.
Human embryonic stem cells (hESCs) provide an important means to characterize early stages of hematopoietic development. However, the in vivo potential of hESC-derived hematopoietic cells has not been well defined. We demonstrate that hESC-derived cells are capable of long-term hematopoietic engraftment when transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Human CD45+ and CD34+ cells are identified in the mouse bone marrow (BM) more than 3 months after injection of hESCs that were allowed to differentiate on S17 stromal cells for 7–24 days. Secondary engraftment studies further confirm long-term repopulating cells derived from hESCs. We also evaluated two mechanisms that may inhibit engraftment: host immunity and requirement for homing to BM. Treatment with anti-ASGM1 antiserum that primarily acts by depletion of natural killer cells in transplanted mice leads to improved engraftment, likely due to low levels of HLA class I expressed on hESCs and CD34+ cells derived from hESCs. Intra-BM injection also provided stable engraftment, with hematopoietic cells identified in both the injected and contra-lateral femur. Importantly, no teratomas are evident in animals injected with differentiated hESCs. These results demonstrate that SCID-repopulating cells, a close surrogate for hematopoietic stem cells, can be derived from hESCs. Moreover, both adaptive and innate immune effector cells may be barriers to engraftment of these cells.
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