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EMBRYONIC STEM CELLS

Immature and Neurally Differentiated Mouse Embryonic Stem Cells Do Not Express a Functional Fas/Fas Ligand System

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

Key Words. Fas • Fas ligand • Fas/Fas ligand system • Embryonic stem cells • Neural differentiation • Immune response Immunosuppression • Brain • Transplantation

Correspondence: Kai-Christian Sonntag, M.D., Ph.D., Harvard Medical School, Center for Neuroregeneration Research, Mailman Research Center 126, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA. Telephone: 617-855-3138; Fax: 617-855-3284; e-mail: kai.sonntag{at}mclean.harvard.edu

Received November 15, 2006; accepted for publication June 27, 2007.
First published online in STEM CELLS EXPRESS   July 5, 2007.



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 central nervous system. Its receptor, Fas, is expressed on various immune-reactive cell types, such as activated natural killer 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 neurodifferentiation and after transplantation to the rat brain without further immunosuppression. Although control transfected HEK-293T cells expressed functional rFasL, immature and differentiated mouse ES cells did not express the recombinant rFasL surface protein. Furthermore, 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.

Disclosure of potential conflicts of interest is found at the end of this article.