M.Sc Thesis

M.Sc StudentKovalev Ekaterina
SubjectIn Vivo Immunogenicity Assessment of Mouse Induced
Pluripotent Stem Cells Derived Cardiomyocytes
DepartmentDepartment of Biotechnology
Supervisor PROF. Lior Gepstein


Heart failure is one of the most promising targets for cell replacement therapy with
induced pluripotent stem cells (iPSCs). Nevertheless, for efficient iPSC-based therapy, it is required that the differentiated cells would not prompt immune rejection that could jeopardize graft survival and function. While it is generally assumed that autologous iPSCs cell-derivatives are immune-tolerant, a previous study has challenged this assumption by demonstrating that undifferentiated mouse iPSCs can be immunogenic in syngeneic hosts.

In this study, we aimed to assess whether differentiated iPSC-CMs would elicit an
immune response resulting in cell-graft rejection following transplantation into the
left ventricular myocardium of syngeneic and allogeneic mice. Our results show:
(1) The ability to induce successful cardiomyocyte differentiation of the newlyestablished mouse iPSC line using the hanging drop method;
(2) Teratomas formed from undifferentiated iPSCs are immunogenic, not only in the
allogeneic model (where all teratomas were rejected and could not be identified) but
also in syngeneic recipients as identified by significant infiltration of immune cells;
(3) Differentiated iPSC-CMs are not immunogenic following transplantation into the
hearts of syngeneic animals, while allogeneic iPSC-CMs evoke severe immune
(4) Significantly higher quantities of iPSC-CMs survive in syngeneic heart
transplantation in comparison to the allogeneic graft;
(5) Very low or no expression of the immunogenic genes Zg16 and Hormad1 were
observed in the differentiated iPSC-CMs, a finding that could explain the absence of
significant immune rejection of these cells following transplantation into the
syngeneic hearts.

We demonstrated that iPSC-CMs do not elicit a significant immune response following transplantations into syngeneic mouse hearts. These encouraging results hold great promise for the development of future autologous myocardial cell replacement therapies and favor the possibility of using autologous patient-specific human iPSC-CMs to treat damaged cardiac tissue, thereby avoiding lifelong immunosuppressive therapy. Further research should be carried out in the field of regenerative medicine in order to optimize graft integration with the host myocardium in order to achieve electromechanical properties restoration of the failing heart.