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Publication : Enhanced in utero allogeneic engraftment in mice after mobilizing fetal HSCs by α4β1/7 inhibition.

First Author  Kim AG Year  2016
Journal  Blood Volume  128
Issue  20 Pages  2457-2461
PubMed ID  27650329 Mgi Jnum  J:237363
Mgi Id  MGI:5812617 Doi  10.1182/blood-2016-06-723981
Citation  Kim AG, et al. (2016) Enhanced in utero allogeneic engraftment in mice after mobilizing fetal HSCs by alpha4beta1/7 inhibition. Blood 128(20):2457-2461
abstractText  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 alpha4beta1 and alpha4beta7 integrin inhibitor (alpha4beta1/7), 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.
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