Date of Award

8-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Chair

Yan-Lin Guo

Committee Chair Department

Biological Sciences

Committee Member 2

Faqing Huang

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Sandra Leal

Committee Member 3 Department

Biological Sciences

Committee Member 4

Mohamed Elasri

Committee Member 4 Department

Biological Sciences

Committee Member 5

Vijay Rangachari

Committee Member 5 Department

Chemistry and Biochemistry

Abstract

Embryonic stem cells (ESCs) have been recognized as a promising cell source for regenerative medicine. Intensive research over the past decade has led to the possibility that ESC-derived cells will be used for the treatment of human diseases. However, increasing evidence indicates that ESC-derived cells generated by the current differentiation methods are not fully functional. It is recently recognized that ESC-derived cells lack innate immunity to a wide range of infectious agents and inflammatory cytokines. When used in patients, ESC-derived cells would be placed in wounded sites that are exposed to various pathogens and inflammatory cytokines; therefore, their viability and functionality would be significantly compromised if the cells do not have competent immunity. The responses of mESCs to three types of live viruses, La Crosse virus, West Nile virus, and Sendai virus, were firstly investigated. The results demonstrated that mESCs were susceptible to the viral infections, but they were unable to express type I interferons (IFNα and IFNβ). The failure of mESCs to express IFNα/β was further demonstrated with polyIC (polyinosinic-polycytidylic acid), a synthetic viral dsRNA analog that strongly induced IFNα/β in 10T1/2 cells. The author conclude that the mechanisms that mediate type I IFN expression are deficient in mESCs. It will be further demonstrated that single stranded RNA and protein encoding mRNA induce strong IFN expression and cytotoxicity in fibroblasts and cancer epithelial cells, but none of these effects associated with antiviral responses was observed in ESCs. Therefore, ESCs are intrinsically deficient in antiviral responses; in particular, they do not have functional mechanisms to express type I IFN. Furthermore, the author found that mESCs can respond to type I IFNs and express IFN-stimulated genes as in differentiated fibroblasts. IFNβ and IFNω can protect mESCs from La Crosse virus-induced cell death and inhibit the replication of LACV and West Nile Virus. In summary, these findings illustrated that the cellular mechanisms for production of and response to type I IFN are not equally developed in mESCs; they are deficient in type I IFN expression but have functional mechanisms that respond to and mediate the antiviral effects of type I IFN.

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