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

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.

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

“…Enhancement of angiogenesis in subdermal tissues is detected in these studies ( 49 , 76 ). ASCs can also be delivered by gene-activated scaffold, in which typical gene related to wound healing process is facilitated ( 52 , 80 ). Laiva et al.…”

“…Suku et al. investigated β-klotho gene-activated scaffold to reduce the release of interleukin-8 to suppress inflammatory process ( 80 ). In addition, gene-modified scaffolds may be more targeted to specific pathological conditions.…”

Dual-Drug Loaded Biomimetic Chitosan-Collagen Hybrid Nanocomposite Scaffolds for Ameliorating Potential Tissue Regeneration in Diabetic Wounds

“…16.480700 doi: bioRxiv preprint and improve its low mechanical strength. Natural polymers are preferred over synthetic polymers because of their outstanding biodegradability and biocompatibility (22) (23).…”

“…Chemical cross-linking or combined hybridization with synthetic polymers or natural polysaccharides are considered effective methodologies for manufacturing superior CLG-based scaffolds to minimize the possibility of CLG degradation and improve its low mechanical strength. Natural polymers are preferred over synthetic polymers because of their outstanding biodegradability and biocompatibility (22) (23). Numerous co- and synthetic polymers have been employed in conjunction with CLG.…”

Anti-Aging β-Klotho Gene-Activated Scaffold Promotes Rejuvenative Wound Healing Response in Human Adipose-Derived Stem Cells

“…However, the ADSCs tend to lose their stemness upon expansion [31]. Previously, we found that an anti-aging protein β-Klotho could significantly improve the proliferation of healthy and diabetic human ADSCs [32]. Most studies generally use the primary variant α-Klotho [33][34][35] and have shown that the protein can increase the lifespan of ADSCs by activating the telomerase transcriptional activity [33].…”