Abstract
Wound healing requires a tight orchestration of complex cellular events. Disruption in the cell-signaling events can severely impair healing. The application of biomaterial scaffolds has shown healing potential; however, the potential is insufficient for optimal wound maturation. This study explored the functional impact of a collagen-chondroitin sulfate scaffold functionalized with nanoparticles carrying an anti-aging gene β-Klotho on human adipose-derived stem cells (ADSCs) for rejuvenative healing applications. We studied the response in the ADSCs in three phases: (1) transcriptional activities of pluripotency factors (Oct-4, Nanog and Sox-2), proliferation marker (Ki-67), wound healing regulators (TGF-β3 and TGF-β1); (2) paracrine bioactivity of the secretome generated by the ADSCs; and (3) regeneration of basement membrane (fibronectin, laminin, and collagen IV proteins) and expression of scar-associated proteins (α-SMA and elastin proteins) towards maturation. Overall, we found that the β-Klotho gene-activated scaffold offers controlled activation of ADSCs’ regenerative abilities. On day 3, the ADSCs on the gene-activated scaffold showed enhanced (2.5-fold) activation of transcription factor Oct-4 that was regulated transiently. This response was accompanied by a 3.6-fold increase in the expression of the anti-fibrotic gene TGF-β3. Through paracrine signaling, the ADSCs-laden gene-activated scaffold also controlled human endothelial angiogenesis and pro-fibrotic response in dermal fibroblasts. Towards maturation, the ADSCs-laden gene-activated scaffold further showed an enhanced regeneration of the basement membrane through increases in laminin (2.1-fold) and collagen IV (8.8-fold) deposition. The ADSCs also expressed 2-fold lower amounts of the scar-associated α-SMA protein with improved qualitative elastin matrix deposition. Collectively, we determined that the β-Klotho gene-activated scaffold possesses tremendous potential for wound healing and could advance stem cell-based therapy for rejuvenative healing applications.
Highlights
Wound healing is a complex biological process that requires a tight orchestration of multiple cellular events [1]
Our finding shows that the adipose-derived stem cells (ADSCs) on the gene-activated scaffold can enhance endothelial sprouting and control their growth through paracrine signaling
Our finding demonstrates that the aged conditioned media (CM) from the gene-activated scaffold group could control the expression of pro-fibrotic collagen I in the adult dermal fibroblasts
Summary
Wound healing is a complex biological process that requires a tight orchestration of multiple cellular events [1]. In the aging population, cellular events are disrupted, leading to delayed healing [2]. Pharmaceuticals 2021, 14, 1168 protect the wound from infection, absorb wound exudates, and keep the wound moist to prevent tissue necrosis [5]. Therapeutics can be loaded into biomaterial scaffolds and promote faster healing in hard-to-heal wounds [1]. Biomaterial scaffolds alone may not effectively orchestrate the multiple signaling cascades occurring within the wound. Delivering stem cells is sometimes proposed as a solution for moderating the complex signaling events in the wound [6]
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