Reprogramming of Dermal Fibroblasts into Osteo-Chondrogenic Cells with Elevated Osteogenic Potency by Defined Transcription Factors.
Reprogramming of Dermal Fibroblasts into Osteo-Chondrogenic Cells with Elevated Osteogenic Potency by Defined Transcription Factors.
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DOI：
10.1016/j.stemcr.2017.04.018
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Cheung M
中科院分区：
文献类型：
--
作者：
Wang Y;Wu MH;Cheung MPL;Sham MH;Akiyama H;Chan D;Cheah KSE;Cheung M
最近的研究使用定义的转录因子将皮肤成纤维细胞转化为软骨细胞，这提出了一个问题，即表达SOX9和RUNX2的骨软骨祖细胞是否也可以在重编程过程中产生。在这里，我们证明了强力霉素诱导的重编程因子（KLF4 [K]和c-MYC [M]）的表达6天足以将小鼠成纤维细胞转化为SOX9+/RUNX2+细胞聚集体，并且在确定的干细胞培养基mTeSR中培养时，与SOX9 (S)一起提高了转化效率。kms重编程细胞具有与天然骨-软骨祖细胞相似的基因表达谱，具有较高的成骨特性，可以在体外分化为成骨细胞和软骨细胞，但在皮肤下和小鼠胫骨骨折部位移植后形成骨组织。总之，我们提供了一种重编程策略，能够有效地衍生成骨软骨细胞，这种细胞替代疗法不仅适用于软骨，也适用于骨组织。SOX9+/RUNX2+结节在软骨重编程过程中产生SOX9+/RUNX2+结节显示成骨软骨细胞的基因表达谱成骨软骨细胞在体外分化为软骨细胞和成骨细胞成骨软骨细胞在体内获得较高的成骨能力张和同事在软骨重编程过程中发现了一个短暂的成骨软骨样细胞状态。这些成骨软骨细胞在体内表现出与天然成骨软骨祖细胞相似的基因表达谱，具有较高的成骨能力。因此，这项研究提供了一种重编程策略来产生骨软骨细胞，这种细胞疗法不仅适用于软骨，也适用于骨组织。
Recent studies using defined transcription factors to convert skin fibroblasts into chondrocytes have raised the question of whether osteo-chondroprogenitors expressing SOX9 and RUNX2 could also be generated during the course of the reprogramming process. Here, we demonstrated that doxycycline-inducible expression of reprogramming factors (KLF4 [K] and c-MYC [M]) for 6 days were sufficient to convert murine fibroblasts into SOX9+/RUNX2+ cellular aggregates and together with SOX9 (S) promoted the conversion efficiency when cultured in a defined stem cell medium, mTeSR. KMS-reprogrammed cells possess gene expression profiles akin to those of native osteo-chondroprogenitors with elevated osteogenic properties and can differentiate into osteoblasts and chondrocytes in vitro, but form bone tissue upon transplantation under the skin and in the fracture site of mouse tibia. Altogether, we provide a reprogramming strategy to enable efficient derivation of osteo-chondrogenic cells that may hold promise for cell replacement therapy not limited to cartilage but also for bone tissues. SOX9+/RUNX2+ nodules are generated during the course of chondrogenic reprogramming SOX9+/RUNX2+ nodules exhibit gene expression profiles of osteo-chondroprogenitors Osteo-chondrogenic cells differentiate into chondrocytes and osteoblasts in vitro Osteo-chondrogenic cells acquire elevated osteogenic potency in vivo Cheung and colleagues identify a transient state of osteo-chondroprogenitor-like cells during the course of chondrogenic reprogramming. These osteo-chondrogenic cells exhibit a gene expression profile akin to that of native osteo-chondroprogenitors with elevated osteogenic potency in vivo. Therefore, this study provides a reprogramming strategy to generate osteo-chondrogenic cells that might be useful for cell-based therapy not limited to cartilage but also for bone tissues.