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
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
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DOI：
10.1182/blood-2008-12-195859
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发表时间：
2009-07-09
期刊：
影响因子：
20.3
通讯作者：
Forlino, Antonella
中科院分区：
文献类型：
--
作者：
Panaroni, Cristina;Gioia, Roberta;Forlino, Antonella
由I型胶原中的甘氨酸取代引起的常染色体显性遗传性骨生成障碍（OI）是干细胞治疗的典型障碍。骨髓移植在OI儿童产生了低植入率，但令人惊讶的是，令人鼓舞的症状改善。子宫内移植（IUT）可能更有希望。然而，迄今为止，这两种方法的系统研究仅限于隐性小鼠模型。在这项研究中，我们评估了子宫内移植成人骨髓到杂合子BrtlIV小鼠。Brt 1是一种敲入小鼠，在I型胶原蛋白[α 1（I）-Gly 349 Cys]中具有经典的甘氨酸取代，显性性状传递，以及类似于中度严重和致死性OI的表型。成年骨髓供体细胞从增强型绿色荧光蛋白（eGFP）转基因小鼠移植到造血和非造血组织分化为小梁和皮质骨细胞，并合成高达20%的所有I型胶原在宿主骨。移植消除了杂合BrtlIV小鼠的围产期致死性。在2月龄时，治疗的Brt 1小鼠的股骨的几何参数有显著改善（P
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 [alpha 1(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