1. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.
- Author
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Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, Kreider J, Leikin S, Vera JC, Mertz EL, Perilli E, Baruffaldi F, Villa I, Farina A, Casasco M, Cetta G, Rossi A, Frattini A, Marini JC, Vezzoni P, and Forlino A
- Subjects
- Animals, Bone Marrow Cells cytology, Collagen metabolism, Disease Models, Animal, Extracellular Space chemistry, Female, Gene Knock-In Techniques, Genes, Dominant, Graft Survival, Mice, Mice, Transgenic, Osteogenesis Imperfecta metabolism, Osteogenesis Imperfecta pathology, Phenotype, Pregnancy, Spectrum Analysis, Raman, Survival Rate, Tissue Donors, Aging physiology, Bone Marrow Transplantation methods, Fetal Research, Osteogenesis Imperfecta prevention & control, Osteogenesis Imperfecta therapy, Uterus physiology
- Abstract
Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases.
- Published
- 2009
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