title: Enhanced in utero allogeneic engraftment in mice after mobilizing fetal HSCs by α4β1/7 inhibition.
abstract: In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor-specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4β1 and α4β7 integrin inhibitor (α4β1/7), have been shown to disrupt HSC retention in the postnatal hematopoietic niche. We hypothesized that maternal administration of AMD3100 and/or firategrast prior to IUHCT would mobilize endogenous HSCs from the fetal liver (FL) and result in preferential FL homing of donor HSCs and enhanced long-term engraftment following IUHCT in an allogeneic mouse model. We demonstrate that (1) both agents cross the placenta with rapidly detectable fetal serum concentrations following maternal administration; (2) firategrast treatment alone or with AMD3100 mobilizes endogenous HSCs from the FL and results in increased FL homing of donor HSCs following IUHCT; and (3) enhanced donor HSC homing following firategrast treatment translates into increased long-term multilineage donor cell engraftment. This approach highlights the potential of mobilization strategies to overcome barriers to successful engraftment and increase the clinical promise of IUHCT.
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Aimee G
authors.initials: AG
authors.lastname: Kim
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Vrecenak
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Boelig
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Linda
authors.initials: L
authors.lastname: Eissenberg
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Rettig
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: John S
authors.initials: JS
authors.lastname: Riley
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Holt
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Conner
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Stavros P
authors.initials: SP
authors.lastname: Loukogeorgakis
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Flake
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: William H
authors.initials: WH
authors.lastname: Peranteau
mesh_terms: D000818:Animals; D005260:Female; D005332:Fetoscopy; D005333:Fetus / Q000166:cytology / Q000276:immunology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7