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Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta

Abstract

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5–2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

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Figure 1: Flow cytometric analysis of cultured osteoblasts to exclude the presence of contaminating lymphohemopoietic cells.
Figure 2: a, Fluorescence in situ hybridization analysis of interphase nuclei from the cultured osteoblasts of patient 1 on day 101 after transplantation.
Figure 3: a, Biopsy specimen of trabecular bone before transplantation, stained with Goldners-Masson trichrome.
Figure 4: a, Growth rates of the patients during the 6 months immediately before (▪) and after (░) transplantation.

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Acknowledgements

We acknowledge J. Marini for discussions throughout this study; and S. Nooner, W. Cabral, B. Hopkins and M. Kinnarney for assistance. We also thank J. Gilbert for his editorial review and J. Johnson for assistance in preparation of this manuscript. This work was supported in part by NHLBI Clinical Investigator Development Award #K08 HL 03266, by Cancer Center Support CORE Grant P30 CA 21765, by the Hartwell Foundation, and by the American Lebanese Syrian Associated Charities (ALSAC).

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Correspondence to Edwin M. Horwitz.

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Horwitz, E., Prockop, D., Fitzpatrick, L. et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5, 309–313 (1999). https://doi.org/10.1038/6529

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