Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta.
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.
Le Blanc
Katarina
K
Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Katarina.leblanc@medhs.ki.se
Götherström
Cecilia
C
Ringdén
Olle
O
Hassan
Moustapha
M
McMahon
Robert
R
Horwitz
Edwin
E
Anneren
Göran
G
Axelsson
Ove
O
Nunn
Janice
J
Ewald
Uwe
U
Nordén-Lindeberg
Solveig
S
Jansson
Monika
M
Dalton
Ann
A
Aström
Eva
E
Westgren
Magnus
M
D000328:Adult; D001706:Biopsy; D001842:Bone and Bones / Q000473:pathology; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D017931:DNA Primers; D005260:Female; D016332:Fetal Tissue Transplantation; D005865:Gestational Age; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008648:Mesoderm; D010013:Osteogenesis Imperfecta / Q000628:therapy*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000628:therapy*; D033581:Stem Cell Transplantation; D018183:Transplantation Chimera
D024042:Collagen Type I; D017931:DNA Primers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D003094:Collagen