Horwitz (1999) - 1999 Nature America Inc....

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NATURE MEDICINE • VOLUME 5 • NUMBER 3 • MARCH 1999 309 ARTICLES Bone marrow contains not only precursors for the hemopoietic system, but also cells that can give rise to mesenchymal lineages, including bone, cartilage and muscle 1–8 . In preclinical models, transplanted marrow-derived mesenchymal cells migrated to and became incorporated into bone and muscle of the recipient animals, indicating that these cells have a ‘homing’ capacity 8–11 . In principle, therefore, bone marrow transplantation could be used to correct a far wider range of inherited and acquired disorders than now occurs. Support for this has come almost ex- clusively from murine models, leaving several principal ques- tions unanswered. It is unknown, for example, whether mesenchymal cells from human marrow are capable of engraft- ing in allogeneic hosts and whether such cells can differentiate and function normally in vivo . To begin to address these ques- tions, we undertook bone marrow transplantation in three pa- tients with osteogenesis imperfecta. Osteogenesis imperfecta (OI) is a genetic disorder of mesenchy- mal cells in which generalized osteopenia leads to bony deformi- ties, excessive fragility with fracturing, and short stature. The underlying defect is a mutation in one of the two genes encoding type I collagen, the primary structural protein of bone 12 . There is no cure for OI, nor is there any proven therapy for alleviating its symptoms 12–14 ; although pamidronate, one of the bisphosphonate compounds, may have some therapeutic potential 15 . We chose this disorder to validate the principle of mesenchymal progenitor cell transplantation because engraftment of mesenchymal cells in a murine model of OI produced a small but appreciable improve- ment in the disease phenotype 16 . Here we demonstrate that mar- row-derived mesenchymal cells can indeed engraft in humans and generate donor-derived osteoblasts that function sufficiently well for 6 months, to attenuate the biochemical, structural and clinical abnormalities associated with OI. Engraftment of hemopoietic and mesenchymal cells Three children with severe deforming OI (Table) were intra- venously infused with unmanipulated bone marrow from HLA- identical or single-antigen-mismatched siblings after they had received ablative conditioning therapy. All three showed en- graftment with hemopoietic donor cells. Patient 1 had a mixed hemopoietic chimerism (21% donor cells) that was stable for more than 6 months. In patients 2 and 3, more than 99% of the hemopoietic cells analyzed were of donor origin. Osteoblasts were cultured from fresh bone biopsy specimens. The individual adherent cells in the cultures had typical osteoblast morphology, expressed alkaline phosphatase and produced stainable matrix. Flow cytometric analysis of these cells indicated a lack of conta-
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Horwitz (1999) - 1999 Nature America Inc....

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