Umrath Felix, Wendt Valerie, Gasparoni Gilles, Narknava Yasser, Walter Jörn, Lethaus Bernd, Weber Josefin, Carriel Victor, Avci-Adali Meltem, Alexander Dorothea
Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany.
Department of Orthopaedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany.
Cells. 2025 Apr 22;14(9):627. doi: 10.3390/cells14090627.
Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells (iMSCs). Using an optimized protocol, we generated iMSCs with a remarkable osteogenic potential while exhibiting lower expression levels of the senescence markers p16 and p21 compared to the original JPCs. This study aimed to explore the epigenetic landscape by comparing the DNA methylation and transcription profiles of iMSCs with their JPC precursors, seeking to uncover key differences. Additionally, this analysis provided an opportunity for us to investigate the potential rejuvenation effects associated with cellular reprogramming. To assess the safety of the generated cells, we evaluated their ability to form teratomas through subcutaneous injection into immunodeficient mice. Our findings revealed that, while the methylation profile of iMSCs closely mirrored that of JPCs, distinct iMSC-specific methylation patterns were evident. Strikingly, the application of DNA methylation (DNAm) clocks for biological age estimation showed a dramatic reduction in DNAm age to approximately zero in iPSCs-a rejuvenation effect that persisted in the derived iMSCs. This profound reset in biological age, together with our transcriptome data, indicate that iMSCs could possess an enhanced regenerative potential compared to adult MSCs. Future in vivo studies should validate this hypothesis.
诱导多能干细胞（iPSC）正迅速成为再生医学中一种具有变革性的资源。在之前的一项研究中，我们实验室取得了一个重要的里程碑，成功地将颌骨骨膜细胞（JPC）重编程为iPSC，然后将其分化为iPSC衍生的间充质干细胞（iMSC）。使用优化的方案，我们生成了具有显著成骨潜力的iMSC，与原始JPC相比，其衰老标志物p16和p21的表达水平较低。本研究旨在通过比较iMSC与其JPC前体的DNA甲基化和转录谱来探索表观遗传景观，试图发现关键差异。此外，该分析为我们研究与细胞重编程相关的潜在年轻化效应提供了机会。为了评估所生成细胞的安全性，我们通过皮下注射到免疫缺陷小鼠中来评估它们形成畸胎瘤的能力。我们的研究结果表明，虽然iMSC的甲基化谱与JPC的甲基化谱密切相似，但明显存在独特的iMSC特异性甲基化模式。引人注目的是，应用DNA甲基化（DNAm）时钟进行生物学年龄估计显示，iPSC中的DNAm年龄显著降低至约零——这种年轻化效应在衍生的iMSC中持续存在。生物学年龄的这种深刻重置，连同我们的转录组数据，表明与成人MSC相比，iMSC可能具有增强的再生潜力。未来的体内研究应验证这一假设。
