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Gene-Activated Scaffold Based Wound Healing

Anti-Ageing Protein β-Klotho Rejuvenates Diabetic Stem Cells for Improved Gene-Activated Scaffold Based Wound Healing

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, they 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. They 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, they 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, their 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.1

Metabolic activity and cell count of normal and diabetic adipose-derived stem cells (ADSCs) after 24 h of β-klotho treatment in 2D: (A) the effect of β-klotho treatment in normal ADSCs. β-klotho at a concentration of 2 µg/mL was found to be optimal for enhancing the growth of normal ADSCs. Treatment with 2 µg/mL β-klotho significantly enhanced the metabolic activity (p < 0.0001) as well proliferation (p < 0.0001) of normal ADSCs compared to the non-treated control. (B) Diabetic ADSCs treated with 2 µg/mL β-klotho also 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.
Metabolic activity and cell count of normal and diabetic adipose-derived stem cells (ADSCs) after 24 h of β-klotho treatment in 2D: (A) the effect of β-klotho treatment in normal ADSCs. β-klotho at a concentration of 2 µg/mL was found to be optimal for enhancing the growth of normal ADSCs. Treatment with 2 µg/mL β-klotho significantly enhanced the metabolic activity (p < 0.0001) as well proliferation (p < 0.0001) of normal ADSCs compared to the non-treated control. (B) Diabetic ADSCs treated with 2 µg/mL β-klotho also 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.

The expression of soluble fibrinogenic and inflammatory factors in normal and diabetic ADSCs cultured on SDF-GAS is shown. (A) Relative expression of fibrinogenic factors: Overall, β-klotho+ ADSCs showed downregulation of fibrinogenic factors compared to its non-treated controls. β-klotho priming markedly reduced (approximately 2-fold) the production of plasminogen activator inhibitor-1 in both (i) normal and (ii) diabetic ADSCs. (B) Relative expression of inflammatory cytokines: (i) β-klotho priming enhanced the production of both interleukin-8 and monocyte chemoattractant protein-1 in normal ADSCs. (ii) β-klotho primed diabetic ADSCs showed downregulation of interleukin-8 while upregulating the production of monocyte chemoattractant protein-1 by ~2-fold compared to the control group. β-klotho+ and β-klotho− refers to β-klotho primed ADSCs and untreated controls respectively.

1 Suku, Meenakshi; Laiva, Ashang L.; O’Brien, Fergal J.; Keogh, Michael B. 2021. "Anti-Ageing Protein β-Klotho Rejuvenates Diabetic Stem Cells for Improved Gene-Activated Scaffold Based Wound Healing" J. Pers. Med. 11, no. 1: 4. https://doi.org/10.3390/jpm11010004