Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model

Dong Li1, Hong Yang1, Hong Nan1, Peng Liu2, Sulei Pang2,Qian Zhao3, Rotem Karni4, Mark P. Kamps5, Yuanfu Xu2, Jiaxi Zhou2,Therese Wiedmer6, Peter J. Sims6, and Fei Wang1,*

Understanding the process of myeloid differentiation offers important insights into both normal and abnormal developmental processes, but is limited by the dearth of experimental models. Here we show that myeloid progenitors can be derived from embryonic stem cells (ESCs), immortalized, and applied to the study of the mechanisms underlying myeloid differentiation. The ESC-derived myeloid progenitors, when immortalized with estrogen-regulated Hoxb8 protein (Hoxb8-ER), demonstrate normal karyotyping, are genetically tractable, and can be differentiated into functional neutrophils. By using this model, we identified Mammalian Target of Rapamycin Complex 1 (mTORC1) as a critical regulator of myeloid differentiation. Together, our studies led to a convenient, karyotypically normal and genetically manipulatable cellular system, which can be used to shed new light on the mechanisms for myeloid differentiation.

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