Faulknor Renea A, Olekson Melissa A, Nativ Nir I, Ghodbane Mehdi, Gray Andrea J, Berthiaume François
Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
Biochem Biophys Res Commun. 2015 Feb 27;458(1):8-13. doi: 10.1016/j.bbrc.2015.01.013. Epub 2015 Jan 24.
During wound healing, fibroblasts deposit extracellular matrix that guides angiogenesis and supports the migration and proliferation of cells that eventually form the scar. They also promote wound closure via differentiation into α-smooth muscle actin (SMA)-expressing myofibroblasts, which cause wound contraction. Low oxygen tension typical of chronic nonhealing wounds inhibits fibroblast collagen production and differentiation. It has been suggested that hypoxic mesenchymal stromal cells (MSCs) secrete factors that promote wound healing in animal models; however, it is unclear whether these factors are equally effective on the target cells in a hypoxic wound environment. Here we investigated the impact of MSC-derived soluble factors on the function of fibroblasts cultured in hypoxic fibroblast-populated collagen lattices (FPCLs). Hypoxia alone significantly decreased FPCL contraction and α-SMA expression. MSC-conditioned medium restored hypoxic FPCL contraction and α-SMA expression to levels similar to normoxic FPCLs. SB431542, an inhibitor of transforming growth factor-β1 (TGF-β1)-mediated signaling, blocked most of the MSC effect on FPCL contraction, while exogenous TGF-β1 at levels similar to that secreted by MSCs reproduced the MSC effect. These results suggest that TGF-β1 is a major paracrine signal secreted by MSCs that can restore fibroblast functions relevant to the wound healing process and that are impaired in hypoxia.
在伤口愈合过程中，成纤维细胞分泌细胞外基质，引导血管生成，并支持最终形成瘢痕的细胞迁移和增殖。它们还通过分化为表达α-平滑肌肌动蛋白（SMA）的肌成纤维细胞来促进伤口闭合，从而引起伤口收缩。慢性不愈合伤口典型的低氧张力会抑制成纤维细胞胶原蛋白的产生和分化。有人提出，低氧间充质基质细胞（MSCs）分泌的因子可促进动物模型中的伤口愈合；然而，尚不清楚这些因子在低氧伤口环境中对靶细胞是否同样有效。在这里，我们研究了MSC衍生的可溶性因子对在低氧成纤维细胞填充的胶原晶格（FPCLs）中培养的成纤维细胞功能的影响。单独的低氧显著降低了FPCL收缩和α-SMA表达。MSC条件培养基将低氧FPCL收缩和α-SMA表达恢复到与常氧FPCLs相似的水平。SB431542，一种转化生长因子-β1（TGF-β1）介导信号的抑制剂，阻断了MSC对FPCL收缩的大部分作用，而与MSC分泌水平相似的外源性TGF-β1重现了MSC的作用。这些结果表明，TGF-β1是MSCs分泌的一种主要旁分泌信号，它可以恢复与伤口愈合过程相关且在低氧状态下受损的成纤维细胞功能。
