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

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, nongenetic 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 NP CF -hCMP group), with hCMPs composed of hiPSC-CMs and empty nanoparticles (the NP E -hCMP group); with patches containing the CHIR99021/FGF-loaded nanoparticles but lacking hiPSC-CMs (the NP CF -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).

Engineering Human Cardiac Muscle Patch Constructs for Prevention of Post-infarction LV Remodeling

“…However, hCMPs of clinically relevant thicknesses require formation of a dense internal vascular network that couples with the native circulation after transplantation (9,157). Vascularization can be increased by including combinations of vascular and other cell types (ECs, SMCs, and/or fibroblasts) (23, 62, 161) during manufacturing and/or via the nanoparticle-mediated (151) extended release of pro-angiogenic factors [e.g., vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and the Wnt activator CHIR99021; (162,163)], which can promote infiltration of the native circulatory system. Further, the spatial orientation of the vascular network can be controlled with more technologically advanced fabrication methods (e.g., micropatterning and 3D bioprinting) to enhance the mass transport and perfusion [(164); Figure 4].…”

“…Overexpression of CCND2 (cyclin D2), a cell cycle activator, increased cell cycle activity and proliferation rate in hiPSC-CMs, thus improving engraftment rate from average 10 to 25% with a significant remuscularization of injured myocardium in mice (203). CM retention could also be enhanced via co-administration of pro-survival factors, such as Matrigel, cyclosporine A, pinacidil, ZVAD-fmk, insulin-like growth factor-1 (IGF-1), CHIR99021, and fibroblast growth factor 1(FGF1) (50,82,163).…”

Nano-Medicine in the Cardiovascular System

“…High biocompatibility and low cytotoxicity are attributed to the degradation byproducts—lactate and glycolate—which can easily be incorporated into cellular metabolic pathways ( Figure 1 ) ( Chereddy et al, 2018 ). Due to these highly desirable properties, PLGA has been widely studied as both a therapeutic and diagnostic agent in the cardiac field as well ( Oduk et al, 2018 ; Zhang et al, 2019 ; Fan et al, 2020a ; Fan et al, 2020b ). With improvements in processing and production techniques, PLGA has also enjoyed a lot of attention due to the relative ease with which comparatively large batches of nano-medicines can be produced via emulsion polymerization.…”

Nanoparticle-Mediated Drug Delivery for Treatment of Ischemic Heart Disease

“…Intravenous injection of collapsin response mediator protein-2 (CRMP2) lipid with the size of 50 nm was shown fibrosis reducing in the mice chronic MI heart ( Zhou et al, 2015 ). For vasculogenesis enhancement, VEGF, FGF1, Ang-1, stromal cell-derived factor-1 (SDF-1) or CCR2 was loaded in NPs and delivered to the ischemic myocardial tissue to stimulate angiogenesis ( Paul et al, 2011 ; Lu et al, 2015 ; Oduk et al, 2018 ; Ding et al, 2020 ; Fan et al, 2020 ). Interestingly, Wang et al (2018) recently reported that no statistically significant improvements in cardiac function and infarct size were detected in mice acute MI heart with the intravenous administration of CCR2 targeting-nanoparticles (micelles) vs. non-targeted micelles.…”