Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta

Abstract

Stem cells have considerable potential to repair damaged organs and tissues. We previously showed that prenatal transplantation of human first trimester fetal blood mesenchymal stem cells (hfMSCs) in a mouse model of osteogenesis imperfecta (oim mice) led to a phenotypic improvement, with a marked decrease in fracture rate. Donor cells differentiated into mature osteoblasts, producing bone proteins and minerals, including collagen type I␣2, which is absent in nontransplanted mice. This led to modifications of the bone matrix and subsequent decrease of bone brittleness, indicating that grafted cells directly contribute to improvement of bone mechanical properties. Nevertheless, the therapeutic effect was incomplete, attributing to the limited level of engraftment in bone. In this study, we show that although migration of hfMSCs to bone and bone marrow is CXCR4-SDF1 (SDF1 is stromal-derived factor) dependent, only a small number of cells present CXCR4 on the cell surface despite high levels of internal CXCR4. Priming with SDF1, however, upregulates CXCR4 to increase the CXCR4 ؉ cell fraction, improving chemotaxis in vitro and enhancing engraftment in vivo at least threefold in both oim and wild-type bone and bone marrow. Higher engraftment in oim bones was associated with decreased bone brittleness. This strategy represents a step to improve the therapeutic benefits of fetal cell therapy toward being curative. STEM CELLS TRANSLATIONAL MED-ICINE 2012;1:70 -78

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

“…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.…”

“…Changes to the bone mechanical properties of transplanted oim were most likely mediated by the exogenous cells since higher engraftment levels in bones correlated with decreased bone stiffness. This is in agreement with recent work from our group showing that upregulation of CXCR4 in transplanted fetal blood MSC increased cell homing to sites of injury via the CXCR4-SDF1 pathway [62,63], which subsequently increased donor cell engraftment in addition to bone plasticity and bone quality [62]. 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.…”

Pre- and Postnatal Transplantation of Fetal Mesenchymal Stem Cells in Osteogenesis Imperfecta: A Two-Center Experience

“…Second, there could still be an immune response toward the infused cells, although we found no evidence of any adaptive cellular response toward the donor cells. Last, specific cellular adhesion molecules present on hfMSCs [43] may regulate more efficient homing to fetal bones than in the postnatal setting.…”

CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

“…Expression of SDF-1 is predominantly promoted under ischemic conditions including AKI (2,19,31,35). However, the surface expression of CXCR4 in BMSCs is markedly reduced during ex vivo expansion (32,40), which may lead to low efficiency of infused BMSCs homing toward the damaged tissues (18,37). Regulation of CXCR4 expression is expected to influence the directional homing of infused BMSCs.…”