Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
Department of Plastic Surgery, Johns Hopkins University, Baltimore, MD, USA.
Stem Cells. 2023 Sep 15;41(9):862-876. doi: 10.1093/stmcls/sxad047.
Numerous intrinsic factors regulate mesenchymal progenitor commitment to a specific cell fate, such as osteogenic or adipogenic lineages. Identification and modulation of novel intrinsic regulatory factors represent an opportunity to harness the regenerative potential of mesenchymal progenitors. In the present study, the transcription factor (TF) ZIC1 was identified to be differentially expressed among adipose compared with skeletal-derived mesenchymal progenitor cells. We observed that ZIC1 overexpression in human mesenchymal progenitors promotes osteogenesis and prevents adipogenesis. ZIC1 knockdown demonstrated the converse effects on cell differentiation. ZIC1 misexpression was associated with altered Hedgehog signaling, and the Hedgehog antagonist cyclopamine reversed the osteo/adipogenic differentiation alterations associated with ZIC1 overexpression. Finally, human mesenchymal progenitor cells with or without ZIC1 overexpression were implanted in an ossicle assay in NOD-SCID gamma mice. ZIC1 overexpression led to significantly increased ossicle formation in comparison to the control, as assessed by radiographic and histologic measures. Together, these data suggest that ZIC1 represents a TF at the center of osteo/adipogenic cell fate determinations-findings that have relevance in the fields of stem cell biology and therapeutic regenerative medicine.
许多内在因素调节间充质祖细胞向特定细胞命运（如成骨或成脂谱系）的分化。鉴定和调节新的内在调节因子代表了利用间充质祖细胞再生潜力的机会。在本研究中，发现转录因子（TF）ZIC1 在脂肪来源的间充质祖细胞与骨骼来源的间充质祖细胞之间存在差异表达。我们观察到，在人骨髓间充质祖细胞中过表达 ZIC1 可促进成骨作用并阻止成脂作用。ZIC1 敲低则表现出对细胞分化的相反作用。ZIC1 的异常表达与 Hedgehog 信号转导改变有关，而 Hedgehog 拮抗剂环巴胺可逆转与 ZIC1 过表达相关的成骨/成脂分化改变。最后，将过表达或未过表达 ZIC1 的人骨髓间充质祖细胞植入 NOD-SCID 伽马小鼠的骨片模型中。与对照组相比，ZIC1 过表达可导致骨片形成明显增加，通过放射学和组织学测量评估。总之，这些数据表明，ZIC1 是决定成骨/成脂细胞命运的 TF 的核心——这些发现与干细胞生物学和治疗再生医学领域相关。
