JAK-STAT3 and somatic cell reprogramming

Abstract

Reprogramming somatic cells to pluripotency, especially by the induced pluripotent stem cell (iPSC) technology, has become widely used today to generate various types of stem cells for research and for regenerative medicine. However the mechanism(s) of reprogramming still need detailed elucidation, including the roles played by the leukemia inhibitory factor (LIF) signaling pathway. LIF is central in maintaining the ground state pluripotency of mouse embryonic stem cells (ESCs) and iPSCs by activating the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway. Characterizing and understanding this pathway holds the key to generate naïve pluripotent human iPSCs which will facilitate the development of patient-specific stem cell therapy. Here we review the historical and recent developments on how LIF signaling pathway regulates ESC pluripotency maintenance and somatic cell reprogramming, with a focus on JAK-STAT3.

Keywords: JAK; LIF; STAT3; embryonic stem cells; epigenetics; iPSC; reprogramming.

Figure 1. Schematic diagram of LIF signaling pathways. LIF binds to LIFR, which leads to the heterodimerization of LIFR and gp130. This is followed by the activation of JAK-STAT3, PI3K/Akt, and Erk1/2 signaling pathways. The activated STAT3 leads to increased expression of SOCS3, which serves as a negative feedback signal to LIF stimulated activation of STAT3 and Erk1/2.

Figure 2. Schematic representation of LIF regulated pluripotency circuit in ESCs. Upon LIF activation, JAK-STAT3 promotes the expression of the core pluripotency circuit (green box) together with PI3K/Akt for pluripotency maintenance. Activated STAT3 also directly suppresses differentiation by inhibiting the expression of lineage commitment genes.

Figure 3. Schematic representation of STAT3 regulated somatic cell reprogramming via epigenetic mechanisms. During late-stage reprogramming, STAT3 orchestrates the epigenetic changes leading to complete pluripotency, by ensuring full activation of core pluripotency genes through promoting DNA demethylation and open chromatin formation, while suppressing the viral transgenes and lineage commitment genes by promoting de novo DNA methylation and probably PRC2 mediated histone modifications.