Genetic Engineering of Mesenchymal Stem Cells to Induce Their Migration and Survival

Abstract

Mesenchymal stem cells (MSCs) are very attractive for regenerative medicine due to their relatively easy derivation and broad range of differentiation capabilities, either naturally or induced through cell engineering. However, efficient methods of delivery to diseased tissues and the long-term survival of grafted cells still need improvement. Here, we review genetic engineering approaches designed to enhance the migratory capacities of MSCs, as well as extend their survival after transplantation by the modulation of prosurvival approaches, including prevention of senescence and apoptosis. We highlight some of the latest examples that explore these pivotal points, which have great relevance in cell-based therapies.

Figure 1

The role of migration in various routes of cell delivery. (a) Intraparenchymal injection triggers inflammatory responses and may augment the host reaction against the graft (arrows). Single stem cell infiltration of brain parenchyma after intraventricular (b) and intra-arterial (c) infusion.

Figure 2

MSCs engineered to enhance migratory properties. Increased MSC migration could be accomplished by membrane-bound receptor engineering (i.e., CXCR1, CXCR4, and CXCR7), water channel receptors (Aqp1), or the upregulation of defined nuclear receptors (i.e., Nur77 and Nurr1).

Figure 3

Proliferative and differentiation potential of MSC engineering. An improvement in the proliferative hallmarks of MSCs could be accomplished by the stimulation of proproliferation genes regulated by Sox2 and Oct4 transcription factors. Furthermore, senescence-related genes could be silenced (i.e., lipocalin-2 production), or oxidative stress resistance might be enhanced (i.e., PSMB5).

Figure 4

MSC prosurvival engineering. Prosurvival strategies primarily target the apoptosis process by downregulation of the elements involved in the apoptotic cascade (i.e., caspase 8 inhibition by miR-155). Other approaches involve the induction of prosurvival genes (i.e., HIF-1α), while still others ensure protection from fluid-stress or complement-mediated lysis.