SDF-1α Gene-Activated Collagen Scaffold Restores Pro-Angiogenic Wound Healing Features in Human Diabetic Adipose-Derived Stem Cells

Abstract

Non-healing diabetic foot ulcers (DFUs) can lead to leg amputation in diabetic patients. Autologous stem cell therapy holds some potential to solve 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). We assessed the impact of the gene-activated scaffold on diabetic ADSCs by comparing their response against healthy ADSCs cultured on a gene-free scaffold over two weeks. Overall, we found that the gene-activated scaffold could restore the 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 gene-activated scaffold induced the overexpression of SDF-1α in diabetic ADSCs and engaged the receptor CXCR7, causing downstream β-arrestin signaling, as effectively as the transfected healthy ADSCs. The transfected diabetic ADSCs also exhibited pro-wound healing features characterized by active matrix remodeling of the provisional fibronectin matrix and basement membrane protein collagen IV. The gene-activated scaffold also induced a controlled pro-healing response in the healthy ADSCs by disabling early developmental factors signaling while promoting the expression of tissue remodeling components. Conclusively, we show that the SDF-1α gene-activated scaffold can overcome the deficiencies associated with diabetic ADSCs, paving the way for autologous stem cell therapies combined with novel biomaterials to treat DFUs.

Diabetic Wound-Healing Science

“…Murine diabetic models have found that the use of adipose- [ 200 ], umbilical- [ 201 ], bone-marrow- [ 202 ], and smooth-muscle [ 203 ]-derived stem cells or combination therapies with MSCs [ 204 , 205 ] accelerated wound healing. As diabetic-derived stem cells have an impaired healing phenotype, modification of MSCs by selective gene overexpression such as stromal-cell-derived factor (SDF)-1α [ 180 ], overexpression of c-Jun [ 181 ], depletion of miR-205-5p [ 103 ], or by photobiomodulation [ 238 ] have shown promising results in promoting wound healing and provides potential pathways for autologous stem cell treatment. In humans, the injection of autologous micro-fragmented adipose tissue [ 239 ] and combination therapies with umbilical cord MSCs improved healing outcomes [ 240 ].…”

Adipose-Derived Stem Cells for the Treatment of Diabetic Wound: From Basic Study to Clinical Application

“…In previous studies, ASCs are inferred to influence the procedure of inflammation in chronic wounds by paracrine effects to suppress inflammation ( 30 ). To further verify the opinion, several studies evaluated the inflammatory cytokine variation in rat ASCs treated diabetic wounds ( 45 , 48 , 52 ). Cytokines such as IL-6, IL-8 are significantly deregulated in diabetic and non-diabetic ASCs treated wounds.…”

“…In a study conducted by Laiva et. al, the application of SDF-1α scaffold, which promotes ASCs proliferation, showed no significant effect on high inflammatory cytokine caused by diabetic ASCs, indicating ASCs do not function as inflammatory cytokine secretion ( 52 ). In pre-clinical studies, human ASCs are used in diabetic wounds.…”

Synergistic Effect of Biomaterial and Stem Cell for Skin Tissue Engineering in Cutaneous Wound Healing: A Concise Review

“…Hence, the SDF-1α gene-activated scaffold can overcome the deficiencies associated with diabetic ADSCs, paving the way for autologous stem cell therapies combined with novel biomaterials to treat DFUs. Moreover, the transfected diabetic ADSCs also exhibited pro-wound healing features like active matrix remodelling of the provisional fibronectin matrix and basement membrane protein collagen IV [ 116 ], which is not only essential for supporting the adhesion and migration of cells, but also provides a scaffold for subsequent collagen deposition [ 126 ]. A similar in vivo study used human-induced pluripotent stem cell-derived smooth muscle cells (hiPSC-SMC) instead of ASC, combined with collagen scaffold to treat diabetic mouse [ 115 ].…”