Maternal administration of busulfan before in utero transplantation of human hematopoietic stem cells enhances engraftments in sheep.
In utero transplantation (IUT) of human hematopoietic stem cells has been conducted in sheep, which are used as large animal models of human hematopoietic reconstitution and models for clinical IUT; however, the levels of engraftment have generally been low. Busulfan (BU), a myeloablative agent, is often administered to patients before hematopoietic stem cells transplantation to improve the engraftment. In this study, hematopoietic activity was evaluated in adult sheep after administering BU at different doses. Next, pregnant ewes were administered BU, and dams as well as their fetuses were evaluated, as BU readily crosses the sheep placenta. Then, the BU dose with the desired outcomes was selected and administered to pregnant ewes at 2 or 6 days before performing IUT using human cord blood CD34(+) cells. The engraftment was evaluated in recipients that underwent IUT in the presence or absence of BU. As a result, hematopoietic activity was safely and transiently suppressed in adult sheep treated with 5 to 7.5 mg/kg BU. BU crossed the sheep placenta, and fetal sheep were indeed conditioned by administering 3 mg/kg BU to pregnant ewes. Engraftment of human CD34(+) cells in fetal recipients was enhanced when IUT was carried out 6 days post-BU. Up to 3.3% engraftment levels (in terms of bone marrow colony-forming units) were achieved with the IUT of 0.72 to 2.4 million CD34(+) cells when BU was used. BU can be administered to pregnant ewes to effectively condition the fetal recipient for IUT with enhanced engraftment of donor cells.
Department of Agriculture, Utsunomiya University, Tochigi, Japan.
Tomoyuki
T
Abe
Shigeo
S
Masuda
Yujiro
Y
Tanaka
Suguru
S
Nitta
Yoshihiro
Y
Kitano
Satoshi
S
Hayashi
Yutaka
Y
Hanazono
Yoshikazu
Y
Nagao
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001483:Base Sequence; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017931:DNA Primers; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008431:Maternal-Fetal Exchange; D023421:Models, Animal; D010920:Placenta / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012756:Sheep; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D002066:Busulfan