Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
HAN University of Applied Sciences, Arnhem, The Netherlands.
Tissue Eng Regen Med. 2024 Dec;21(8):1173-1187. doi: 10.1007/s13770-024-00667-9. Epub 2024 Aug 31.
The developmental abnormality spina bifida is hallmarked by missing tissues (e.g. skin) and exposure of the spinal cord to the amniotic fluid, which can negatively impact neurological development. Surgical closure of the skin in utero limits neurological damage, but in large defects this results in scarring and contractures. Stimulating skin regeneration in utero would greatly benefit treatment outcome. Previously, we demonstrated that a porous type I collagen (COL) scaffold, functionalized with heparin (HEP), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) (COL-HEP/GF) improved pre- and postnatal skin regeneration in a fetal sheep full thickness wound model. In this study we uncover the early events associated with enhanced skin regeneration.
We investigated the gene expression profiles of healing fetal skin wounds two weeks after implantation of the COL(-HEP/GF) scaffolds. Using laser dissection and microarrays, differentially expressed genes (DEG) were identified in the epidermis and dermis between untreated wounds, COL-treated wounds and wounds treated with COL-HEP/GF. Biological processes were identified using gene enrichment analysis and DEG were clustered using protein-protein-interaction networks.
COL-HEP/GF influences various interesting biological processes involved in wound healing. Although the changes were modest, using protein-protein-interaction networks we identified a variety of clustered genes that indicate COL-HEP/GF induces a tight but subtle control over cell signaling and extracellular matrix organization.
These data offer a novel perspective on the key processes involved in (fetal) wound healing, where a targeted and early interference during wound healing can result in long-term enhanced effects on skin regeneration.
神经管缺陷性脊柱裂的发育异常的特征是组织缺失（例如皮肤）和脊髓暴露于羊水，这会对神经发育产生负面影响。在子宫内闭合皮肤可以限制神经损伤，但在大的缺陷中，这会导致疤痕和挛缩。在子宫内刺激皮肤再生将极大地有益于治疗效果。以前，我们证明了一种多孔的 I 型胶原蛋白（COL）支架，通过肝素（HEP）、成纤维细胞生长因子 2（FGF2）和血管内皮生长因子（VEGF）功能化（COL-HEP/GF），改善了胎儿羊全层伤口模型的产前和产后皮肤再生。在这项研究中，我们揭示了与增强皮肤再生相关的早期事件。
我们研究了植入 COL(-HEP/GF)支架后两周愈合胎儿皮肤伤口的基因表达谱。使用激光解剖和微阵列，在未处理的伤口、COL 处理的伤口和 COL-HEP/GF 处理的伤口之间，鉴定表皮和真皮中的差异表达基因（DEG）。使用基因富集分析鉴定生物学过程，并使用蛋白质-蛋白质相互作用网络对 DEG 进行聚类。
COL-HEP/GF 影响各种与伤口愈合相关的有趣生物学过程。尽管变化不大，但使用蛋白质-蛋白质相互作用网络，我们鉴定了各种聚类基因，这些基因表明 COL-HEP/GF 对细胞信号和细胞外基质组织的调控既紧密又微妙。
这些数据为（胎儿）伤口愈合中涉及的关键过程提供了新的视角，在伤口愈合过程中进行有针对性和早期的干预，可以对皮肤再生产生长期的增强效果。
