Factors that influence short-term homing of human bone marrow-derived mesenchymal stem cells in a xenogeneic animal model

Abstract

Human mesenchymal stem cells are potential agents for tissue regeneration, enhancing hematopoietic stem cell transplantation and delivering genes of therapeutic interest. To implement any of these strategies successfully, we need a better understanding of factors that influence the tissue distribution of systemically administered mesenchymal stem cells. The present study was designed to investigate the short-term tissue homing of mesenchymal stem cells in immunodeficient mouse models, exploring the effects of animal age, duration of ex vivo expansion of mesenchymal stem cells, lentiviral transduction and CXCR4 over-expression. Dye-labeled mesenchymal stem cells (1.5-2.0 x 10(6)/animal) were injected via the tail vein into unconditioned beta2m/NOD/SCID animals. Animals were sacrificed 20-24 hours later and cell suspensions from tissues were examined by flow cytometry for the presence of PKH-positive cells. PKH-positive cells were readily detected in the bone marrow, spleen, liver and lungs at 20-24 hours after infusion. The homing of systemically infused mesenchymal stem cells to the bone marrow and spleen of unconditioned beta2m/NOD/SCID animals was significantly (>2-fold, p<0.001) higher in younger (<10 weeks) animals, and was reduced with increasing passage number. Despite low surface CXCR4 expression, human mesenchymal stem cells migrated to SDF-1 in vitro, and this was enhanced by over-expression of CXCR4 using lentiviral transduction. Over-expression of CXCR4 by lentiviral transduction (>80%) did not alter the bone marrow homing of mesenchymal stem cells in unconditioned animals, but caused a significant (p<0.05) increase in homing to bone marrow and spleen of animals that had received prior irradiation. Tissue homing of systemically administered mesenchymal stem cells is influenced by host factors such as age, is diminished by prolonged in vitro culture, and can be increased by enforced expression of CXCR4, at least in irradiated hosts.