Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta

被引:339
作者
Le Blanc, K [1 ]
Götherström, C
Ringdén, O
Hassan, M
McMahon, R
Horwitz, E
Anneren, G
Axelsson, O
Nunn, J
Ewald, U
Nordén-Lindeberg, S
Jansson, M
Dalton, A
Åström, E
Westgren, M
机构
[1] Karolinska Univ Hosp Huddinge, Div Clin Immunol, Ctr Allogen Stem Cell Transplantat, Karolinska Inst, SE-14186 Stockholm, Sweden
[2] Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Fetal Med, Dept Hematol, Stockholm, Sweden
[3] Sheffield Childrens NHS Trust, Western Bank, N Trent Mol Genet Lab, Sheffield, S Yorkshire, England
[4] St Jude Res Hosp, Div Stem Cell Transplantat, Dept Hematol & Oncol, Memphis, TN USA
[5] St Jude Res Hosp, Dept Expt Hematol, Memphis, TN USA
[6] Uppsala Univ, Dept Clin Genet, Uppsala, Sweden
[7] Uppsala Univ, Women & Childrens Hlth, Uppsala, Sweden
关键词
osteogenesis imperfecta; mesenchymal stem cells; in utero transplantation; fetal transplantation; tolerance; immunity;
D O I
10.1097/01.TP.0000159029.48678.93
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Mesenchymal stem cells (MSC) are progenitors of mesenchymal tissues such as bone, cartilage, and adipose. Adult human leukocyte antigen (HLA)-matched MSC have been used in cellular therapies of bone disorders such as osteogenesis imperfecta, with promising results. Methods. A female fetus with multiple intrauterine fractures, diagnosed as severe osteogenesis imperfecta, underwent transplantation with allogeneic HLA-mismatched male fetal MSC in the 32nd week of gestation. Engraftment analyses of donor cells, immunologic reaction against donor cells, and the well-being of the patient were assessed. Results. At 9 months of age, on slides stained for osteocalcin or osteopontin, a centromeric XY-specific probe revealed 0.3% of XY-positive cells in a bone biopsy specimen. Whole Y genome fluorescent in situ hybridization staining showed a median of 7.4% Y-positive cells (range, 6.8%-16.6%). Bone histology showed regularly arranged and configurated bone trabeculae. Patient lymphocyte proliferation against donor MSC was not observed in co-culture experiments performed in vitro after MSC injection. Complementary bisphosphonate treatment was begun at 4 months. During the first 2 years of life, three fractures were noted. At 2 years of corrected age, psychomotor development was normal and growth followed the same channel, -5 SD. Conclusions. The authors' findings show that allogeneic fetal MSC can engraft and differentiate into bone in a human fetus even when the recipient is immunocompetent and HLA-incompatible.
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收藏
页码:1607 / 1614
页数:8
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