title: Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.
abstract: Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of the allogeneic iPSC-cardiac. This imaging tool may enable the understanding and monitoring host-immune response of the host, allogeneic cell transplantation therapy.
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kashiyama
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akima
authors.initials: A
authors.lastname: Harada
authors.affiliation: Dept. Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan.|PET Molecular Imaging Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Dept. Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Toda
authors.affiliation: Dept. Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan.|PET Molecular Imaging Center, Osaka University Graduate School of Medicine, Osaka, Japan.|Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hatazawa
authors.affiliation: Dept. Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D006084:Graft Rejection / Q000000981:diagnostic imaging*; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000473:pathology / Q000637:transplantation*; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D014184:Transplantation, Homologous; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053583:Interleukin-1beta; D011720:Pyrazoles; D011743:Pyrimidines; D018079:Receptors, GABA; C463819:Bzrp protein, mouse; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide