For hundreds of indications, mesenchymal stromal cells (MSCs) have not achieved the expected therapeutic efficacy due to an inability of the cells to reach target tissues. We show that inducing high
mannose N-
glycans either chemically, using the
mannosidase I inhibitor
Kifunensine, or genetically, using an
shRNA to silence the expression of
mannosidase I A1 (MAN1A1), strongly increases the motility of MSCs. We show that treatment of MSCs with
Kifunensine increases cell migration toward
bone fracture sites after percutaneous injection, and toward lungs after
intravenous injection. Mechanistically, high
mannose N-
glycans reduce the contact area of cells with its substrate. Silencing MAN1A1 also makes cells softer, suggesting that an increase of high
mannose N-glycoforms may change the physical properties of the cell membrane. To determine if treatment with
Kifunensine is feasible for future clinical studies, we used mass spectrometry to analyze the N-
glycan profile of MSCs over time and demonstrate that the effect of
Kifunensine is both transitory and at the expense of specific N-glycoforms, including fucosylations. Finally, we also investigated the effect of
Kifunensine on cell proliferation, differentiation, and the secretion profile of MSCs. Our results support the notion of inducing high
mannose N-
glycans in MSCs in order to enhance their migration potential.