Immature and Neurally Differentiated Mouse ES Cells Do Not Express A Functional Fas/Fasl System

¹ Center for Neuroregeneration Research, Udall Parkinson's Disease Center of Excellence, McLean Hospital, Harvard Medical School, Belmont, MA

^* To whom correspondence should be addressed. E-mail: kai.sonntag{at}mclean.harvard.edu.

	Abstract

The potential of pluripotent embryonic stem (ES) cells to develop into functional cells or tissue provides an opportunity in the development of new therapies for many diseases including neurodegenerative disorders. The survival of implanted cells usually requires systemic immunosuppression, however, which severely compromises the host immune system leading to complications in clinical transplantation. An optimal therapy would therefore be the induction of specific tolerance to the donor cells, while otherwise preserving functional immune responses. Fas ligand (FasL) is expressed in activated lymphocytes as well as cells in "immune-privileged" sites including the CNS. Its receptor Fas is expressed on various immune-reactive cell types, such as activated NK and T cells, monocytes, and polymorphic mononucleocytes, which can undergo apoptosis upon interaction with FasL. To render transplanted cells tolerant to host cellular immune responses, we genetically engineered mouse ES cells to express rat FasL (rFasL). The rFasL-expressing ES cells were analyzed for survival during in vitro neuro-differentiation and after transplantation to the rat brain without further immunosuppression. While control transfected HEK-293T cells expressed functional rFasL, immature and differentiated mouse ES cells did not express the recombinant rFasL surface protein. Further, there was no evidence for functional endogenous Fas and FasL expression on either ES cells or on neural cells after in vitro differentiation. Moreover, implanted rFasL-engineered ES cells did not survive in the rat brains in the absence of the immunosuppressive agent Cyclosporine A. Our results indicate that immature and differentiated mouse ES cells do not express a functional Fas/FasL system.

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