Yeola Avani, Subramanian Shruthi, Oliver Rema A, Lucas Christine A, Thoms Julie A I, Yan Feng, Olivier Jake, Chacon Diego, Tursky Melinda L, Srivastava Pallavi, Potas Jason R, Hung Tzongtyng, Power Carl, Hardy Philip, Ma David D, Kilian Kristopher A, McCarroll Joshua, Kavallaris Maria, Hesson Luke B, Beck Dominik, Curtis David J, Wong Jason W H, Hardeman Edna C, Walsh William R, Mobbs Ralph, Chandrakanthan Vashe, Pimanda John E
Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
Sci Adv. 2021 Jan 13;7(3). doi: 10.1126/sciadv.abd1929. Print 2021 Jan.
Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissue-derived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocyte-derived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.
终末分化的小鼠骨细胞和脂肪细胞可通过血小板衍生生长因子AB和5-氮杂胞苷重编程为具有基质细胞特征的多能干细胞。我们现在已经优化了培养条件，将人类脂肪细胞重编程为诱导多能干细胞（iMS细胞），并对其分子和功能特性进行了表征。尽管脂肪细胞来源的iMS细胞和脂肪组织来源的间充质干细胞的基础转录组相似，但顺式调控区域的组蛋白修饰和CpG甲基化发生了变化，这与为组织发育和分化做好准备的表观遗传景观一致。在非特异性组织损伤异种移植模型中，iMS细胞直接参与肌肉、骨骼、软骨和血管的形成，没有致畸潜能的证据。在心脏毒素肌肉损伤模型中，iMS细胞特异性地参与卫星细胞和肌纤维的形成，没有异位组织形成。总之，人类脂肪细胞来源的iMS细胞以依赖于环境的方式再生组织，不会出现异位或肿瘤生长。
