title: In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.
abstract: Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on embryonic days 13.5 to 14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased because of higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
authors.forename: S Christopher
authors.initials: SC
authors.lastname: Derderian
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
authors.forename: P Priya
authors.initials: PP
authors.lastname: Togarrati
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
authors.forename: Charmin
authors.initials: C
authors.lastname: King
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
authors.forename: Patriss W
authors.initials: PW
authors.lastname: Moradi
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and.
authors.forename: Damien
authors.initials: D
authors.lastname: Reynaud
authors.affiliation: The Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; and.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Czechowicz
authors.affiliation: The Institute of Stem Cell Biology and Regenerative Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
authors.forename: Tippi C
authors.initials: TC
authors.lastname: MacKenzie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D053686:Fetal Stem Cells / Q000166:cytology* / Q000276:immunology; D046128:Fetal Therapies / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology; D055153:Stem Cell Niche / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D019009:Proto-Oncogene Proteins c-kit