Genetically modified adipose tissue−derived mesenchymal stem cells overexpressing CXCR4 display increased motility, invasiveness, and homing to bone marrow of NOD/SCID mice

CXCR4-transduced mesenchymal stem cells protect mice against graft-versus-host disease

“…After overexpressing CXCR4 on MSCs by lentiviral gene transfer, we observed enhanced migration of these cells towards an SDF-1 chemokine gradient, consistent with previous studies with human BM derived MSCs or adipose tissue derived MSCs [29,36,37]. In Matrigel invasion assays, BobisWozowicz et al [36] and Zhang et al [37] have demonstrated that the increased migration of CXCR4-modified MSCs is related to increase production of MMP-2, MMP-9 and TIMP-1, which regulates the degradation of extracellular matrix proteins. Additionally, activation of CXCR4 modulates very late antigens-4 (VLA-4) adhesion to VCAM-1 in vitro, which also plays an important role in BM cell migration [38].…”

“…However, both human and mouse MSCs express low levels of surface CXCR4 after in vitro expansion [34,35]. After overexpressing CXCR4 on MSCs by lentiviral gene transfer, we observed enhanced migration of these cells towards an SDF-1 chemokine gradient, consistent with previous studies with human BM derived MSCs or adipose tissue derived MSCs [29,36,37]. In Matrigel invasion assays, BobisWozowicz et al [36] and Zhang et al [37] have demonstrated that the increased migration of CXCR4-modified MSCs is related to increase production of MMP-2, MMP-9 and TIMP-1, which regulates the degradation of extracellular matrix proteins.…”

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

“…Viral transduction is the most efficient method for obtaining high and stable expression levels in the target cells. CXCR4 overexpression resulted in improved MSC homing to the bone marrow after intracardiac injection into a NOD/SCID transplant model [112] . In a similar model, the overexpression of integrin α4, a subunit of VLA4 that interacts with VCAM-1, also resulted in increased bone marrow homing [113] .…”

“…Because the CXCR4-SDF1 axis is important for bone marrow homing [20,112] , many groups have designed transfection or transduction experiments in which CXCR4 expression plasmids are either nonvirally or virally introduced into the cells. Viral transduction is the most efficient method for obtaining high and stable expression levels in the target cells.…”

Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?

“…Chen et al observed the same in vitro and in vivo correlation for CXCR4 transduced murine MSC transplanted into irradiated BALB/c mice [45]. Moreover Bobis-Wozowikz described that transplantation of CXCR4-transduced human AT-MSC into nonobese NOD/SCID mice led to increased engraftment (0.3% to 0.7% after 24hrs) into BM in comparison to GFP-transduced AT-MSC [46]. Together these data indicate that the CXCL12/CXCR4 axis plays an important role in homing of MSC to the BM, and prior treatment.…”