Date of Completion

8-28-2014

Embargo Period

8-19-2024

Keywords

Human embryonic stem cells, Human induced pluripotent stem cells, Type I IFNs, SOCS1, Innate immunity

Major Advisor

Dr. Gordon G. Carmichael

Associate Advisor

Dr. Stormy J. Chamberlain

Associate Advisor

Dr. James (Yuanhao) Li

Associate Advisor

Dr. Blanka Rogina

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

We have been interested in how human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) respond to double-stranded RNA (dsRNA) and to type I interferons (IFN-α/β). We have shown that, compared to their differentiated counterparts, pluripotent human cells have a much weaker response to cytoplasmic dsRNA, and are only able to produce a minimal amount of IFN-β. In differentiated cells, the type I IFN produced binds to cell surface receptors IFNAR1 and IFNAR2 and triggers a signaling cascade that leads to the transcription of hundreds of IFN-stimulated genes (ISGs). This response is a crucial component in innate immunity in that it establishes an “antiviral state” in cells and protects them against further damage. Our recent studies have revealed that hESCs and hiPSCs also exhibit a greatly attenuated response to IFN-β. Interestingly, even though all known type I IFN signaling components are expressed in these cells, STAT1 phosphorylation does not occur upon IFN-β treatment. This attenuated response correlates with a high expression of suppressor of cytokine signaling 1 (SOCS1). Upon differentiation of hESCs into trophoblasts, cells acquire the ability to respond to IFN-β, and this is accompanied by a significant induction of STAT1 phosphorylation as well as a decrease in SOCS1 expression. Furthermore, SOCS1 knockdown in hiPSCs enhances their ability to respond to IFN-β. Taken together, our results suggest that an attenuated cellular response to type I IFNs may be a general feature of pluripotent human cells. As has been seen for other aspects of stem cell biology, they also appear to be “poised” for future innate immune responses.

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