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Blood. 2014 Aug 7;124(6):973-80. doi: 10.1182/blood-2014-02-550327. Epub 2014 May 30.

In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and The Department of Surgery, University of California, San Francisco, San Francisco, CA;
2
Eli and Edythe Broad Center of Regeneration Medicine and.
3
The Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; and.
4
The Institute of Stem Cell Biology and Regenerative Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA.

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.

PMID:
24879814
PMCID:
PMC4126335
DOI:
10.1182/blood-2014-02-550327
[Indexed for MEDLINE]
Free PMC Article

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