Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity

PROJECT SUMMARY/ABSTRACT
The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Alix
Berglund, DVM, PhD, with the necessary knowledge, training, and experience to become an independent
translational biomedical researcher in the fields of immunology and mesenchymal stem cell (MSC) biology.
MSCs are a promising cell source for treating inflammatory and immune-mediated diseases. Allogeneic therapy
would provide cost-effective and efficient treatment, but is currently hindered by recipient immune rejection of
donor MSCs expressing mismatched-major histocompatibility complex (MHC) molecules. MSCs are strongly
immunomodulatory, however, and manipulation of MHC expression may be sufficient to allow donor MSCs to
evade recipient immune responses. The central hypothesis of this proposal, which is supported by strong
preliminary research, is that treating MSCs with transforming growth factor-β2 (TGF-β2) downregulates MHC I
and MHC II gene transcription thereby reducing the in vivo immunogenicity of MHC-mismatched MSCs. The
aims of this project are to 1) Identify how TGF-β2 downregulates MHC expression in MSCs and 2) Determine
how TGF-β2 treatment affects MSC immunogenicity in vivo. Both murine and equine MSCs will be utilized to
elucidate TGF-β2 signaling pathways to increase translational potential to humans (Aim 1) and non-inflammatory
and inflammatory murine models will be used to analyze how the immune system responds to TGF-β2-treated
MSCs in vivo (Aim 2). Completion of the proposed research is a first step towards improving the efficacy and
safety of allogeneic MSCs for clinical use. To accomplish these aims, Dr. Berglund will build on her background
in mesenchymal stem cell biology, immunology, and large animal models by developing expertise in molecular
immunology techniques, in vivo alloimmune response analysis, and the utilization of murine models. Dr.
Berglund's mentoring team has combined expertise in immunology, mesenchymal stem cells, and genetics to
facilitate her transition to an independent translational biomedical researcher. This work will be completed
primarily at the North Carolina State University College of Veterinary Medicine, which is eminently qualified to
train translational clinician scientists, with additional work at the University of North Carolina-Chapel Hill.