Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China.
J Cell Biochem. 2014 Feb;115(2):359-67. doi: 10.1002/jcb.24670.
Collagen is the most abundant structural protein in mammals and is expressed in various tissues. In recent years, sphingosine 1-phosphate receptors (S1PRs) have been proven to play an important role in the regulation of collagen expression. Our previous studies reported that S1PRs are involved in TGF-β1-induced collagen expression via up-regulating S1PR1/3 in mouse bone marrow-derived mesenchymal stem cells (BMSCs), and result in experimental mouse liver fibrogenesis. But it remains unclear whether this process happens in human bone marrow-derived mesenchymal stem cells (hMSCs). In this study, we provide evidences that S1PR1/3, but not S1PR2, negatively regulate the expression of collagen in hMSCs using cellular and molecular approaches in vitro. We find that treatment of hMSCs with TGF-β1 up-regulated collagen expression in a dose- and time-dependent manner. Meanwhile, TGF-β1 inhibited the expression of S1PR1/3, but not S1PR2, in hMSCs in a time-dependent manner. Furthermore, either selective knock-down of S1PR1 or silencing S1PR3 induced collagen α1(I) and collagen α1(III) expression in hMSCs. In contrast, inhibition of S1PR2 by siRNA had no effects on the expression of collagen. Altogether, all these findings demonstrated that collagen expression was negatively regulated by S1PR1 and S1PR3 in hMSCs. This study highlights the differences between hMSCs and mouse BMSCs, provides a new regulation mechanism for collagen expression, and points out the risk of utilizing hMSCs in clinical applications.
胶原蛋白是哺乳动物中最丰富的结构蛋白，存在于各种组织中。近年来，已证实鞘氨醇 1-磷酸受体（S1PRs）在调节胶原蛋白表达方面发挥着重要作用。我们之前的研究报告称，S1PRs 通过上调小鼠骨髓间充质干细胞（BMSCs）中的 S1PR1/3 参与 TGF-β1 诱导的胶原蛋白表达，导致实验性小鼠肝纤维化。但尚不清楚这一过程是否发生在人骨髓间充质干细胞（hMSCs）中。在这项研究中，我们通过体外细胞和分子方法提供了证据，证明 S1PR1/3 而非 S1PR2 负调节 hMSCs 中胶原蛋白的表达。我们发现 TGF-β1 以剂量和时间依赖的方式上调 hMSCs 中胶原蛋白的表达。同时，TGF-β1 以时间依赖的方式抑制 hMSCs 中 S1PR1/3 的表达，但不抑制 S1PR2 的表达。此外，S1PR1 的选择性敲低或 S1PR3 的沉默诱导 hMSCs 中胶原蛋白 α1(I)和胶原蛋白 α1(III)的表达。相比之下，siRNA 抑制 S1PR2 对胶原蛋白的表达没有影响。总之，所有这些发现表明 S1PR1 和 S1PR3 在 hMSCs 中负调节胶原蛋白表达。这项研究强调了 hMSCs 和小鼠 BMSCs 之间的差异，为胶原蛋白表达提供了新的调节机制，并指出了在临床应用中利用 hMSCs 的风险。
