Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties

Abstract

Osteogenesis imperfecta (OI or brittle bone disease) is a disorder of connective tissues caused by mutations in the collagen genes. We previously showed that intrauterine transplantation of human blood fetal stem/stromal cells in OI mice (oim) resulted in a significant reduction of bone fracture. This work examines the cellular mechanisms and mechanical bone modifications underlying these therapeutic effects, particularly examining the direct effects of donor collagen expression on bone material properties. In this study, we found an 84% reduction in femoral fractures in transplanted oim mice. Fetal blood stem/stromal cells engrafted in bones, differentiated into mature osteoblasts, expressed osteocalcin, and produced COL1a2 protein, which is absent in oim mice. The presence of normal collagen decreased hydroxyproline content in bones, altered the apatite crystal structure, increased the bone matrix stiffness, and reduced bone brittleness. In conclusion, expression of normal collagen from mature osteoblast of donor origin significantly decreased bone brittleness by improving the mechanical integrity of the bone at the molecular, tissue, and whole bone levels.

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

“…Sex-dependent differences in skeletal muscle development in these mice were also noted [18]. Increased mineral-to-matrix ratio in the males is consistent with the increased density reported in younger oim/oim males in the same background [36], studied here. Increased mineral-tomatrix ratio observed in both genders of oim/oim mice indicates a lower matrix content rather than excessive mineralization.…”

“…Rao et al [33] also found gender differences in response of pamidronate-treated oim/oim mice with females showing a greater reduction in bone length in response to higher doses. Vanleene et al [36] also found that female human fetal bone stem/stromal cell transplantation into male and female oim/oim mice responded differently with females showing an increase in carbonate content and males an increase in crystallinity.…”

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

“…Transplanted e-CSC homed to areas of bone growth and fracture repair and expressed osteoblast differentiation genes Osteopontin and Osteocalcin and the COL1A2 protein, indicating their differentiation to functional osteoblasts. These findings are in agreement with previous studies in the oim model that demonstrated the direct differentiation of transplanted cells to osteoblasts [13][14][15][16] and subsequent improvements in disease pathology. In addition, we used the detection of human factor IX as an immunoassay to detect the presence of mouse anti-human antibodies in the serum of mice transplanted with human cells and we were able to show the absence of immune reaction against allogeneic cells.…”

“…These results are in line with our previous studies [15,16,62]. Fracture reduction in e-CSC transplanted mice was attributed to an increase in bone plasticity, as previously demonstrated [23], and greater bone ductility.…”

“…In rodent OI models, transplantation of whole bone marrow/bone marrow MSC led to increased collagen content [11], improved bone strength, reduced perinatal lethality [12], and increased osteoblast differentiation [13,14]. Marked therapeutic benefits were shown following transplantation of fetal MSC from human first trimester blood in a mouse model of human type III OI (oim) including improved bone plasticity and a two-third reduction in long bone fractures [15,16].…”