Background:

Diabetic foot ulcer is one of the leading causes of leg amputation and mortality in diabetic patients. Autologous stem cell therapy holds some potential to be a solution to this problem, however diabetic stem cells are relatively dysfunctional and restrictive in their wound healing abilities. This study sought to explore if a novel collagen-chondroitin sulfate (coll-CS) scaffold functionalized with polyplex nanoparticles carrying the gene encoding for stromal-derived factor-1 alpha (SDF-1α gene-activated scaffold) can enhance the regenerative functionality of human diabetic adipose-derived stem cells (ADSCs). Methods Gene-activated scaffolds were first prepared by soak-loading polyethyleneimine nanoparticles carrying the plasmid encoding for SDF-1α gene into a freeze-dried coll-CS scaffold. ADSCs from healthy and diabetic donors were then seeded on the gene-activated scaffold. The response of the ADSCs in the gene-activated scaffold was then compared against those of the healthy ADSCs cultured on the gene-free scaffold over 2 weeks period. Functional response in the ADSCs such as the activation of SDF-1α mediated signaling, production of bioactive factors, pro-angiogenic bioactivity of secreted factors, matrix deposition and remodeling was determined using proteome profiling, Matrigel assay, qRT-PCR and immunofluorescence. Results Overall, we found that SDF-1α gene-activated scaffold could restore pro-angiogenic regenerative response in the human diabetic ADSCs similar to the healthy ADSCs on the gene-free scaffold. Gene and protein expression analysis revealed that the SDF-1α gene-activated scaffold induced the overexpression of SDF-1α in diabetic ADSCs and engaged the receptor CXCR7, causing downstream signaling of β-arrestin as effectively as the transfected healthy ADSCs. The transfected diabetic ADSCs also effectively stimulated angiogenesis in endothelial cells while undergoing matrix remodeling characterized by reduction in deposition of fibronectin matrix and increase in the expression of basement membrane protein collagen IV. The SDF-1α gene-activated scaffold also induced a controlled pro- healing response in the healthy ADSCs by disabling the signaling of early developmental factors while promoting the expression of tissue remodeling components. Conclusion We show that the SDF-1α gene-activated scaffold can overcome the deficiencies associated with diabetic ADSCs paving the way for autologous patient stem cell therapies in combination with novel biomaterials to treat diabetic foot ulcers.