Abstract
RationaleTissue engineering is a promising alternative for urethral reconstruction, and adipose-derived stem cells (ADSCs) are widely used as seeding cells. Hypoxia preconditioning can significantly enhance the therapeutic effects of ADSCs. The low oxygen tension of postoperative wound healing is inevitable and may facilitate the nutritional function of ADSCs. This study aimed to investigate if hypoxia-preconditioned ADSCs, compared to normoxia-preconditioned ADSCs, combined with scaffold could better promote urethral reconstruction and exploring the underlying mechanism.MethodsIn vitro, paracrine cytokines and secretomes that were secreted by hypoxia- or normoxia-preconditioned ADSCs were added to cultures of human umbilical vein endothelial cells (HUVECs) to measure their functions. In vivo, hypoxia- or normoxia-preconditioned ADSCs were seeded on a porous nanofibrous scaffold for urethral repair on a defect model in rabbits.ResultsThe in vitro results showed that hypoxia could enhance the secretion of VEGFA by ADSCs, and hypoxia-preconditioned ADSCs could enhance the viability, proliferation, migration, angiogenesis, and glycolysis of HUVECs (p < 0.05). After silencing VEGFA, angiogenesis and glycolysis were significantly inhibited (p < 0.05). The in vivo results showed that compared to normoxia-preconditioned ADSCs, hypoxia-preconditioned ADSCs combined with scaffolds led to a larger urethral lumen diameter, preserved urethral morphology, and enhanced angiogenesis (p < 0.05).ConclusionsHypoxia preconditioning of ADSCs combined with scaffold could better promote urethral reconstruction by upregulating angiogenesis and glycolysis. Hypoxia-preconditioned ADSCs combined with novel scaffold may provide a promising alternative treatment for urethral reconstruction.
Highlights
A variety of diseases, such as congenital diseases, malignancies, and trauma, can lead to anterior urethral defects or strictures, which severely influence the physical condition and quality of life of patients [1]
The in vivo results showed that compared to normoxia-preconditioned Adipose-derived stem cells (ADSCs), hypoxia-preconditioned ADSCs combined with scaffolds led to a larger urethral lumen diameter, preserved urethral morphology, and enhanced angiogenesis (p < 0.05)
Hypoxia preconditioning of ADSCs combined with scaffold could better promote urethral reconstruction by upregulating angiogenesis and glycolysis
Summary
A variety of diseases, such as congenital diseases, malignancies, and trauma, can lead to anterior urethral defects or strictures, which severely influence the physical condition and quality of life of patients [1]. Buccal mucosa and penile skin are the most popular tissues used to repair urethral defects in the clinic. Many studies have demonstrated that cell-seeded biomaterials might be an effective method and show great promise in urethral reconstruction [3, 4]. Various growth factors and bioactive cytokines are released to stimulate the growth of nearby cells by paracrine signaling [7, 8]. For this reason, recent studies have focused on how to increase the paracrine activities of stem cells to improve angiogenesis and blood flow recovery for tissue regeneration [9, 10]
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