Amelioration of a mouse model of osteogenesis imperfecta with hematopoietic stem cell transplantation: Microcomputed tomography studies

Abstract

To test the hypothesis that hematopoietic stem cells (HSCs) generate bone cells using bone marrow (BM) cell transplantation in a mouse model of osteogenesis imperfecta (OI). OI is a genetic disorder resulting from abnormal amount and/or structure of type I collagen and is characterized by osteopenia, fragile bones, and skeletal deformities. Homozygous OI murine mice (oim; B6C3Fe a/a-Col1a2(oim)/J) offer excellent recipients for transplantation of normal HSCs, because fast turnover of osteoprogenitors has been shown. We transplanted BM mononuclear cells or 50 BM cells highly enriched for HSCs from transgenic enhanced green fluorescent protein mice into irradiated oim mice and analyzed changes in bone parameters using longitudinal microcomputed tomography. Dramatic improvements were observed in three-dimensional microcomputed tomography images of these bones 3 to 6 months post-transplantation when the mice showed high levels of hematopoietic engraftment. Histomorphometric assessment of the bone parameters, such as trabecular structure and cortical width, supported observations from three-dimensional images. There was an increase in bone volume, trabecular number, and trabecular thickness with a concomitant decrease in trabecular spacing. Analysis of a nonengrafted mouse or a mouse that was transplanted with BM cells from oim mice showed continued deterioration in the bone parameters. The engrafted mice gained weight and became less prone to spontaneous fractures while the control mice worsened clinically and eventually developed kyphosis. These findings strongly support the concept that HSCs generate bone cells. Furthermore, they are consistent with observations from clinical transplantation studies and suggest therapeutic potentials of HSCs in OI.