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

• Published in: Blood Vol. 114; no. 2; pp. 459 - 468
• Main Authors: Panaroni, Cristina, Gioia, Roberta, Lupi, Anna, Besio, Roberta, Goldstein, Steven A., Kreider, Jaclynn, Leikin, Sergey, Vera, Juan Carlos, Mertz, Edward L., Perilli, Egon, Baruffaldi, Fabio, Villa, Isabella, Farina, Aurora, Casasco, Marco, Cetta, Giuseppe, Rossi, Antonio, Frattini, Annalisa, Marini, Joan C., Vezzoni, Paolo, Forlino, Antonella
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 09.07.2009; Americain Society of Hematology; American Society of Hematology
• Series: Transplantation
• Subjects: Aging - physiology; Animals; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Transplantation - methods; Collagen - metabolism; Disease Models, Animal; Diseases of the osteoarticular system; Extracellular Space - chemistry; Female; Fetal Research; Gene Knock-In Techniques; Genes, Dominant; Graft Survival; Hematologic and hematopoietic diseases; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mice; Mice, Transgenic; Osteogenesis Imperfecta - metabolism; Osteogenesis Imperfecta - pathology; Osteogenesis Imperfecta - prevention & control; Osteogenesis Imperfecta - therapy; Phenotype; Pregnancy; Spectrum Analysis, Raman; Survival Rate; Tissue Donors; Transplantation; Uterus - physiology; Human; Animal model; Hematology; Stem cell; Diseases of the osteoarticular system; Rodentia; Hematopoietic cell; Homograft; Perinatal; In utero; Genetic disease; Osteoarticular system; Vertebrata; Phenotype; Mammalia; Mouse; Bone marrow; Osteogenesis imperfecta; Graft; Adult; Bone; Osteochondrodysplasia
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-12-195859

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 [α1(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.