Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States.
Integrative Bioinformatics, Biostatistics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States.
Stem Cells. 2024 Aug 1;42(8):706-719. doi: 10.1093/stmcls/sxae039.
The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for induced pluripotent stem cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small-molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.
从成纤维细胞间充质细胞状态向上皮样状态的转变对于诱导多能干细胞（iPSC）重编程至关重要。在本报告中，我们描述了小分子抑制剂 PFI-3 的研究，该抑制剂特异性靶向 SWI/SNF 复合物的 SMARCA2/4 和 PBRM1 亚基的溴结构域，作为提高 iPSC 重编程效率的增强剂。我们的发现揭示了 PFI-3 在多种人真皮成纤维细胞中诱导细胞可塑性，导致 iPSC 形成过程中的间质上皮转化。这种转化的特征是 E-钙黏蛋白表达的上调，E-钙黏蛋白是参与上皮细胞黏附的关键蛋白。此外，我们确定 COL11A1 是重编程的障碍，并证明 COL11A1 的敲低增加了重编程效率。值得注意的是，我们发现 PFI-3 显著降低了许多细胞外基质（ECM）基因的表达，特别是那些参与胶原蛋白组装的基因。我们的研究为 iPSC 重编程的早期阶段提供了重要的见解，强调了 ECM 变化和细胞可塑性在这一过程中的关键作用。
