CHIR99021 and fibroblast growth factor 1 enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice. (April 2020)

• Record Type: Journal Article
• Authors: Fan, Chengming; Tang, Yawen; Zhao, Meng; Lou, Xi; Pretorius, Danielle; Menasche, Philippe; Zhu, Wuqiang; Zhang, Jianyi
• Is Part Of: Journal of molecular and cellular cardiology. Volume 141(2020)
• Page Start: 1
• Page End: 10
• Publication Date: 2020-04
• Subjects: CHIR99021 -- FGF1 -- Nanoparticle -- Patch -- Stem cell -- Cell cycle -- Myocardial infarction -- Heart failure; hiPSC-CMs Human induced pluripotent stem cell-derived cardiomyocytes -- hCMP Patch containing human induced pluripotent stem cell-derived cardiomyocytes -- NPCF-hCMP hCMP containing hiPSC-CMs and nanoparticles formulated with CHIR99021 and FGF1 -- NPE-hCMP hCMP containing hiPSC-CMs and empty nanoparticles -- NPCF-Patch Patch containing nanoparticles formulated with CHIR99021 and FGF1 but lacking cells -- E-Patch Patch lacking both nanoparticles and cells -- BZ Border zone -- IZ Infarct zone -- MI Myocardial infarction -- RZ Remote zone -- EF Ejection fraction -- FS Fractional shortening; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.03.003
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: We have shown that genetic overexpression of cell cycle proteins can increase the proliferation of transplanted cardiomyocytes derived from human induced-pluripotent stem cells (hiPSC-CMs) in animal models of myocardial infarction (MI). Here, we introduce a new, non-genetic approach to promote hiPSC-CM cell cycle activity and proliferation in transplanted human cardiomyocyte patches (hCMPs). Methods: Mice were randomly distributed into 5 experimental groups (n = 10 per group). One group underwent Sham surgery, and the other 4 groups underwent MI induction surgery followed by treatment with hCMPs composed of hiPSC-CMs and nanoparticles that contained CHIR99021 and FGF1 (the NPCF -hCMP group), with hCMPs composed of hiPSC-CMs and empty nanoparticles (the NPE -hCMP group); with patches containing the CHIR99021/FGF-loaded nanoparticles but lacking hiPSC-CMs (the NPCF -Patch group), or patches lacking both the nanoparticles and cells (the E-Patch group). Cell cycle activity was evaluated via Ki67 and Aurora B expression, bromodeoxyuridine incorporation, and phosphorylated histone 3 levels (immunofluorescence); engraftment via human cardiac troponin T or human nuclear antigen expression (immunofluorescence) and bioluminescence imaging; cardiac function via echocardiography; infarct size and wall thickness via histology; angiogenesis via isolectin B4 expression (immunofluorescence); and apoptosis via TUNEL and caspace 3 expression (immunofluorescence). Results: Combined CHIR99021- and FGF1-treatment significantly increased hiPSC-CM cell cycle activity both in cultured cells (by 4- to 6-fold) and in transplanted hCMPs, and compared to treatment with NPE -hCMPs, NPCF -hCMP transplantation increased hiPSC-CM engraftment by ~4-fold and was associated with significantly better measurements of cardiac function, infarct size, wall thickness, angiogenesis, and hiPSC-CM apoptosis four weeks after MI induction. Conclusions: Nanoparticle-mediated CHIR99021 and FGF1 delivery promotes hiPSC-CM cell cycle activity and proliferation, as well as the engraftment and regenerative potency of transplanted hCMPs, in a mouse MI model. Highlights: CHIR99021 and FGF1 promotes cell cycle activity and proliferation of hiPSC-CMs. We engineered a hCMP with hiPSC-CMs and nanoparticles formulated with the chemicals. hCMP transplantation results in improved graft size and cardiac function in MI mice. These hCMPs are potentially useful in hiPSC-based therapy for myocardial repair.