Preconditioning of mesenchymal stem cells for improved transplantation efficacy in recessive dystrophic epidermolysis bullosa.

[dystrophic epidermolysis bullosa]

The use of hematopoietic cell transplantation (HCT ) has previously been shown to ameliorate cutaneous blistering in pediatric patients with recessive dystrophic epidermolysis bullosa (RDEB ), an inherited skin disorder that results from loss -of-function mutations in COL 7 A 1 and manifests as deficient or absent type VII collagen protein (C 7 ) within the epidermal basement membrane . Mesenchymal stem cells (MSCs ) found within the HCT graft are believed to be partially responsible for this amelioration , in part due to their intrinsic immunomodulatory and trophic properties and also because they have been shown to restore C 7 protein following intradermal injections in models of RDEB . However , MSCs have not yet been demonstrated to improve disease severity as a stand-alone systemic infusion therapy . Improving the efficacy and functional utility of MSCs via a pre-transplant conditioning regimen may bring systemic MSC infusions closer to clinical practice .M SCs were isolated from 2 - to 4 -week -old mice and treated with varying concentrations of transforming growth factor -beta (TGF-beta ; 5 -20 ng /mL ), tumor necrosis factor - alpha (TNF -alpha ; 10 -40 ng /mL ), and stromal cell-derived factor 1 -alpha (SDF-1 alpha ; 30 ng /mL ) for 24 -72 hours .We demonstrate that treating murine MSCs with exogenous TGF-beta (15 ng /mL ) and TNF -alpha (30 ng /mL ) for 48 hours induces an 8 -fold increase in Col 7 a 1 expression and a significant increase in secretion of C 7 protein , and that the effects of these cytokines are both time and concentration dependent . This cytokine treatment also promotes a 4 -fold increase in Tsg-6 expression , a gene whose product is associated with improved wound-healing and immunosuppressive features . Finally , the addition of exogenous SDF-1 alpha to this regimen induces a simultaneous upregulation of Col 7 a 1 , Tsg-6 , and Cxcr 4 expression .These data suggest that preconditioning represents a feasible method for improving the functional utility of MSCs in the context of RDEB stem cell transplantation , and also highlight the applicability of preconditioning principles toward other cell-based therapies aimed at treating RDEB patients .

Diseases
Validation

Diseases presenting "inherited skin disorder that results from loss-of-function mutations" symptom

dystrophic epidermolysis bullosa

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