Notch-mediated maintenance and expansion of human bone marrow stromal/stem cells: A technology designed for orthopedic regenerative medicine

Human bone marrow-derived stromal/stem cells (BMSCs) have great therapeutic potential for treating skeletal disease and facilitating skeletal repair, although maintaining their multipotency and expanding these cells exvivo have proven difficult. Because most stem cell-based applications toskel-etal regeneration and repair in the clinic would require large numbers of functional BMSCs, recent research has focused on methods for the appropriateselection, expansion, and maintenance of BMSC populations during long-term culture. We describe here a novel biological method that entails selection of human BMSCs basedon NOTCH2 expression and activation ofthe NOTCH signaling pathway in cultured BMSCs via at issue cultureplate coated with recombinant human JAGGED1 (JAG1) ligand. We demonstrate that transient JAG1-mediated NOTCH signaling promotes human BMSC maintenance and expansion while increasing their skeletogenic differentiation capacity, both ex vivo and in vivo. This study is the firstof its kindtodescribe aNOTCH-mediated methodology for the maintenance and expansion of human BMSCs and will serve as a platform for future clinical or translational studies aimed at skeletal regeneration and repair.