title: Hematopoietic engraftment of human embryonic stem cell-derived cells is regulated by recipient innate immunity.
abstract: 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.
authors.affiliation: Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Tian
authors.forename: Petter S
authors.initials: PS
authors.lastname: Woll
authors.forename: Julie K
authors.initials: JK
authors.lastname: Morris
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Linehan
authors.forename: Dan S
authors.initials: DS
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D007106:Immune Sera