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TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction
Wangping Chen, … , Jinfu Yang, Jianyi Zhang
Wangping Chen, … , Jinfu Yang, Jianyi Zhang
Published October 22, 2021
Citation Information: JCI Insight. 2021;6(20):e151987. https://doi.org/10.1172/jci.insight.151987.
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Research Article Cardiology Therapeutics

TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction

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Abstract

The meager regenerative capacity of adult mammalian hearts appears to be driven by the proliferation of endogenous cardiomyocytes; thus, strategies targeting mechanisms of cardiomyocyte cell cycle regulation, such as the Hippo/Yes-associated protein (Hippo/Yap) pathway, could lead to the development of promising therapies for heart disease. The pharmacological product TT-10 increases cardiomyocyte proliferation by upregulating nuclear Yap levels. When intraperitoneal injections of TT-10 were administered to infarcted mouse hearts, the treatment promoted cardiomyocyte proliferation and was associated with declines in infarct size 1 week after administration, but cardiac function worsened at later time points. Here, we investigated whether encapsulating TT-10 into poly-lactic-co-glycolic acid nanoparticles (NPs) before administration could extend the duration of TT-10 delivery and improve the potency of TT-10 for myocardial repair. TT-10 was released from the TT-10–loaded NPs for up to 4 weeks in vitro, and intramyocardial injections of TT-10–delivered NPs stably improved cardiac function from week 1 to week 4 after administration to infarcted mouse hearts. TT-10–delivered NP treatment was also associated with significantly smaller infarcts at week 4, with increases in cardiomyocyte proliferation and nuclear Yap abundance and with declines in cardiomyocyte apoptosis. Thus, NP-mediated delivery appears to enhance both the potency and durability of TT-10 treatment for myocardial repair.

Authors

Wangping Chen, Danielle Pretorius, Yang Zhou, Yuji Nakada, Jinfu Yang, Jianyi Zhang

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Figure 1

TT-10 increased cell cycle activity and proliferation in cultured hiPSC-CMs.

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TT-10 increased cell cycle activity and proliferation in cultured hiPSC-...
(A) TT-10 (C11H10FN3OS2; molecular weight, 283.34 Da) contains 4 C=C, 1 C=N, and 1 C=O double bond. Maximum UV/Vis absorbance is approximately 200 nm. (B–E) hiPSC-CMs were cultured under standard conditions (–) or treated with varying concentrations of TT-10 (2 μM, 10 μM, 20 μM, or 100 μM) for 48 hours and immunofluorescently stained for the human isoform of cardiac troponin T (hcTnT). Nuclei were identified by staining with DAPI or with DAPI and Nkx2.5 antibodies. (B) Proliferation was evaluated via immunofluorescence costaining for Ki67 and quantified as the percentage of Ki67-positive cells. (C) hiPSC-CMs in the S phase of the cell cycle were identified via immunofluorescence costaining for BrdU incorporation and quantified as the percentage of BrdU-positive cells. (D) hiPSC-CMs in the M phase of the cell cycle were identified via immunofluorescence costaining for PH3 and quantified as the percentage of PH3-positive cells. (E) hiPSC-CMs undergoing cytokinesis were identified via immunofluorescence costaining for Aurora B (AuB) and quantified as the percentage of AuB-positive cells. Scale bar: 20 μm. All experiments were repeated 5 times. *P < 0.01, **P < 0.05, 1-way ANOVA with Tukey’s correction.

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