Targeted delivery of adipocytokines into the heart by induced adipocyte cell-sheet transplantation yields immune tolerance and functional recovery in autoimmune-associated myocarditis in rats.
BACKGROUND
Clinical prognosis is critically poor in fulminant myocarditis, while it's initiation or progression is fated, in part, by T cell-mediated autoimmunity. Adiponectin (APN) and associated adipokines were shown to be immune tolerance inducers, although the clinically relevant delivery method into target pathologies is under debate. Whether the cell sheet-based delivery system of adipokines might induce immune tolerance and functional recovery in experimental autoimmune myocarditis (EAM) was tested.


RESULTS
Scaffold-free-induced adipocyte cell-sheet (iACS) was generated by differentiating adipose tissue-derived syngeneic stromal vascular-fraction cells into adipocytes on temperature-responsive dishes. Rats with EAM underwent iACS implantation or sham operation. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells in vitro. Immunohistolabelling showed that the iACS implantation elevated the levels of APN and HGF in the myocardium compared to the sham operation, which attenuated the immunological response by inhibiting CD68-positive macropharges and CD4-positive T-cells and activating Foxp3-positive regulatory T cells. Consequently, left ventricular ejection fraction was significantly greater after the iACS implantation than after the sham operation, in association with less collagen accumulation.


CONCLUSIONS
The targeted delivery of adipokines using tissue-engineered iACS ameliorated cardiac performance of the EAM rat model via effector T cell suppression and induction of immune tolerance. These findings might suggest a potential of this tissue-engineered drug delivery system in treating fulminant myocarditis in the clinical setting.
Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine.
Sokichi
S
Kamata
Shigeru
S
Miyagawa
Satsuki
S
Fukushima
Yukiko
Y
Imanishi
Atsuhiro
A
Saito
Norikazu
N
Maeda
Iichiro
I
Shimomura
Yoshiki
Y
Sawa
D017667:Adipocytes / Q000378:metabolism / Q000637:transplantation*; D054392:Adipokines / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D052242:Adiponectin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016503:Drug Delivery Systems; D006321:Heart; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007108:Immune Tolerance; D064596:Isografts / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000494:pharmacology; D013318:Stroke Volume; D023822:Tissue Engineering; D016042:Transplantation, Heterotopic; D014185:Transplantation, Isogeneic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D054392:Adipokines; D052242:Adiponectin; D017077:Culture Media, Conditioned; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D003094:Collagen