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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1717-1725.
Prepublished online as a Blood First Edition Paper on October 29, 2007; DOI 10.1182/blood-2007-08-105809.
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Submitted August 7, 2007
Accepted October 20, 2007
Intrauterine transplantation of human fetal mesenchymal stem cells from first trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice
Pascale V Guillot*, Oyebode Abass, J.H. Duncan Bassett, Sandra J. Shefelbine, George Bou-Gharios, Jerry Chan, Hitoshi Kurata, Graham R. Williams, Julia Polak, and Nicholas M Fisk
Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
Division of Medicine and MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
Department of Bioengineering, Imperial College London, London, United Kingdom
Renal Medicine, Imperial College London, London, United Kingdom
Centre for Fetal Care, Queen Charlotte's & Chelsea Hospital, London, United Kingdom
Tissue Engineering and Regenerative Medicine Center, Imperial College London, London, United Kingdom
* Corresponding author; email: pascale.guillot{at}imperial.ac.uk.
The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted homozygous oim mice in utero with human first trimester fetal blood mesenchymal stem cells (MSC). This resulted in a 2/3 reduction in long bone fractures (P<0.01), with fewer fractures per mouse (median 1, range 0-2, in transplanted vs. 3, 1-5, in untransplanted mice by 12 weeks, P<0.01). Nearly all untransplanted mice had fractures (47/48, 97.9%), in contrast to 17/29 (58.6%) transplanted 4-12 week-old mice (P<0.01). Transplantation was associated with increased bone strength (P<0.01), thickness (P<0.01) and length (P<0.01), with normalisation/reduction of growth plate height in 4-12 week-old oim was reduced in transplanted mice (P<0.001). More donor cells were found in bone tissues compared to other organs (P<0.001), with cells clustered in areas of active bone formation and remodelling, and at sites of fracture healing. Donor cells found in bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSC markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity Type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.
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