Abstract
Skin wounds can lead to serious morbidity complications in diabetic patients due to the reduced healing potential of autologous stem cells. One reason for the low functional potency of stem cells from diabetic patients (diabetic stem cells) is attributed to their senescent-like nature. Here, we investigated if an anti-ageing protein, β-klotho, could be used to rejuvenate diabetic stem cells and to promote pro-angiogenic gene-activated scaffold (GAS)-induced functional response for wound healing applications. Human stem cells derived from the adipose tissue (adipose-derived stem cells (ADSCs)) of normal and diabetic (type 2) donors were used for the study. We report that the β-klotho priming facilitated inflammatory signal pruning by reducing interleukin-8 release by more than half while concurrently doubling the release of monocyte chemoattractant protein-1. Additionally, β-klotho priming enhanced the pro-angiogenic response of diabetic ADSCs on GAS by dampening the release of anti-angiogenic factors (i.e., pigment epithelium-derived factor, tissue inhibitor of metalloproteinase-1 and thrombospondin-1) while simultaneously supporting the expression of pro-angiogenic factors (i.e., Vascular Endothelial Growth Factor (VEGF), angiopoietin-2 and angiogenin). Finally, we show that β-klotho pre-treatment expedites the cellular expression of matrix proteins such as collagen IV and collagen VI, which are implicated in tissue maturation. Taken together, our study provides evidence that the synergistic effect of the pro-angiogenic GAS and β-klotho activation effectively accelerates the functional development of diabetic ADSCs for wound healing applications.
Highlights
With the average life expectancy increasing worldwide, the prevalence of chronic, age-related diseases is increasing
Treatment with 2 μg/mL β-klotho significantly enhanced the metabolic activity (p < 0.0001) as well proliferation (p < 0.0001) of normal adipose-derived stem cells (ADSCs) compared to the non-treated control. (B) Diabetic ADSCs treated with 2 μg/mL β-klotho displayed a significantly higher metabolic activity (i) as well as proliferation (ii) than the non-treated control (p < 0.0001). **** indicates statistical significance of p < 0.0001. β-klotho+ and β-klotho− refers to β-klotho primed ADSCs and untreated controls respectively
We show that β-klotho priming facilitated enhanced production of monocyte chemoattractant protein-1 in diabetic ADSCs, suggesting improved regulation of inflammatory signalling in diabetic ADSCs
Summary
With the average life expectancy increasing worldwide, the prevalence of chronic, age-related diseases is increasing. Diabetic wounds often show delayed wound healing response as a result of dysfunctional fibroblast and epidermal cells, failed angiogenesis and tissue maturation [4]. The application of therapeutics such as growth factor and gene delivery are prospective ways to achieve this. One potential avenue for treating chronic wounds is by entrapping therapeutic genetic material within a scaffold to obtain a gene-activated scaffold (GAS). Delivery of cell-seeded scaffolds into wound sites has been shown to allow for faster tissue regeneration [9]. A cell-seeded GAS that creates a biomimetic cell niche could be of great potential in the treatment of chronic wounds. One such GAS has recently been developed within our laboratory.
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