title: Placental drug delivery for treatment of congenital hematopoietic disorders.
abstract: OBJECTIVE
  The success of in utero hematopoietic cell transplantation (IUHCTx) hinges on successful conditioning strategies of the host to overcome barriers to engraftment. The "space" barrier is a reflection of a finite number of hematopoietic stem cell (HSC) niches within the host. Independent of the number of donor HSCs transplanted, engraftment is frequently low. By conditioning fetal mice using a monoclonal antibody against the c-kit receptor (ACK2) found on HSCs, we can effectively increase space for donor HSC engraftment. We questioned whether simple placental injection of ACK2 early in gestation could effectively deplete host HSCs within the fetal liver and neonatal bone marrow.
  
  
  METHODS
  In this set of experiments, we injected mice with ACK2 (5 μg/fetus) or PBS at E11.5-12.5 and harvested the fetal liver at 2 and 4 days and the neonatal bone marrow at 7 days following injection. Survival and total number of HSCs within the fetal liver or bone marrow were quantified and compared.
  
  
  RESULTS
  Survival between the treated and control group was similar (73% and 71%, respectively). The total number of HSCs within the fetal liver was not significantly lower following ACK2 treatment compared to PBS injected fetuses at 2 days but was by 4 days. Additionally, ACK2 resulted in a significant reduction in the number of HSCs within neonatal mice 7 days after treatment.
  
  
  CONCLUSIONS
  Survival following placental ACK2 injection is comparable to control animals and provides a simple non-invasive strategy to deliver ACK2 into the fetal circulation which successfully depletes the host HSCs.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine, The Department of Surgery, University of California, San Francisco, CA, USA.
authors.forename: S Christopher
authors.initials: SC
authors.lastname: Derderian
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine, The Department of Surgery, University of California, San Francisco, CA, USA.
authors.forename: P Wais
authors.initials: PW
authors.lastname: Moradi
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine, The Department of Surgery, University of California, San Francisco, CA, USA. Electronic address: Tippi.Mackenzie@ucsfmedctr.org.
authors.forename: Tippi C
authors.initials: TC
authors.lastname: MacKenzie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D005333:Fetus / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007267:Injections; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D019009:Proto-Oncogene Proteins c-kit
keywords: ACK2; Hematopoietic niche; IUHCTx; In utero hematopoietic cell transplantation; c-kit