Santarella Francesco, Sridharan Rukmani, Marinkovic Milica, Do Amaral Ronaldo Jose Farias Correa, Cavanagh Brenton, Smith Avi, Kashpur Olga, Gerami-Naini Behzad, Garlick Jonathan A, O'Brien Fergal J, Kearney Cathal J
Royal College of Surgeons in Ireland, 123 St Stephen's Green, Saint Peter's, Dublin, D02 YN77, Ireland.
Biomedical Sciences, National University of Ireland Galway, Newcastle Road, Galway, H91 W2TY, Ireland.
Adv Healthc Mater. 2020 Aug;9(16):e2000307. doi: 10.1002/adhm.202000307. Epub 2020 Jun 29.
Diabetic foot ulcers (DFUs) are chronic wounds, with 20% of cases resulting in amputation, despite intervention. A recently approved tissue engineering product-a cell-free collagen-glycosaminoglycan (GAG) scaffold-demonstrates 50% success, motivating its functionalization with extracellular matrix (ECM). Induced pluripotent stem cell (iPSC) technology reprograms somatic cells into an embryonic-like state. Recent findings describe how iPSCs-derived fibroblasts ("post-iPSF") are proangiogenic, produce more ECM than their somatic precursors ("pre-iPSF"), and their ECM has characteristics of foetal ECM (a wound regeneration advantage, as fetuses heal scar-free). ECM production is 45% higher from post-iPSF and has favorable components (e.g., Collagen I and III, and fibronectin). Herein, a freeze-dried scaffold using ECM grown by post-iPSF cells (Post-iPSF Coll) is developed and tested vs precursors ECM-activated scaffolds (Pre-iPSF Coll). When seeded with healthy or DFU fibroblasts, both ECM-derived scaffolds have more diverse ECM and more robust immune responses to cues. Post-iPSF-Coll had higher GAG, higher cell content, higher Vascular Endothelial Growth Factor (VEGF) in DFUs, and higher Interleukin-1-receptor antagonist (IL-1ra) vs. pre-iPSF Coll. This work constitutes the first step in exploiting ECM from iPSF for tissue engineering scaffolds.
糖尿病足溃疡（DFUs）是慢性伤口，尽管进行了干预，但仍有20%的病例会导致截肢。一种最近获批的组织工程产品——无细胞胶原-糖胺聚糖（GAG）支架——成功率为50%，这促使人们对其进行细胞外基质（ECM）功能化。诱导多能干细胞（iPSC）技术将体细胞重编程为类似胚胎的状态。最近的研究结果描述了iPSC来源的成纤维细胞（“iPSF后体细胞”）如何促进血管生成，比其体细胞前体（“iPSF前体细胞”）产生更多的ECM，并且它们的ECM具有胎儿ECM的特征（这是伤口再生的优势，因为胎儿愈合后不留疤痕）。iPSF后体细胞产生的ECM高出45%，且具有有利的成分（如I型和III型胶原蛋白以及纤连蛋白）。在此，开发了一种使用iPSF后体细胞生长的ECM制成的冻干支架（iPSF后体细胞胶原支架），并与前体细胞ECM激活的支架（iPSF前体细胞胶原支架）进行对比测试。当接种健康或糖尿病足溃疡成纤维细胞时，两种ECM来源的支架都具有更多样化的ECM，并且对信号的免疫反应更强。与iPSF前体细胞胶原支架相比，iPSF后体细胞胶原支架的GAG含量更高、细胞含量更高、糖尿病足溃疡中的血管内皮生长因子（VEGF）更高以及白细胞介素-1受体拮抗剂（IL-1ra）更高。这项工作是利用iPSF来源的ECM用于组织工程支架的第一步。
