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

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

doi:10.1172/jci.insight.151987

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.

Highlights

The endogenous regenerative capacity of adult mammalian hearts is exceptionally limited [1] and cannot replace the cardiomyocytes that are lost to myocardial infarction (MI) or other cardiac disorders
Because p-Yap is sequestered and degraded in the cytosol, while unphosphorylated Yap translocates to the nucleus where it induces the expression of genes that regulate cell proliferation and survival, these results suggest that the effect of TT-10 treatment on cell cycle progression and apoptosis in cultured cardiomyocytes was likely mediated, at least in part, by increases in Yap signaling
Therapies targeting the mechanisms that regulate cell cycle activity may be among the most useful strategies for replacing the myocardial scar with functional contractile tissue, and because this approach mimics the endogenous mechanism of cardiomyocyte renewal, the newly generated cells are likely to be better integrated with the native tissue than exogenously administered cells or engineered tissues

Summary

Introduction

The endogenous regenerative capacity of adult mammalian hearts is exceptionally limited [1] and cannot replace the cardiomyocytes that are lost to myocardial infarction (MI) or other cardiac disorders. Recovery appeared to be driven primarily by the proliferation of preexisting cardiomyocytes, suggesting that postnatal cardiomyocytes retain some latent capacity for proliferation and that strategies targeting mechanisms of cardiomyocyte cell cycle regulation could lead to the development of promising new therapies for heart disease. The pharmaceutical product TT-10 (C11H10FN3OS2) is a fluorine substituent of TAZ-12, and it appears to promote cardiomyocyte proliferation: in mice, intraperitoneal injections of TT-10 reduced infarct size 1 week after MI but did not prevent progressive declines in cardiac function at later time points [7]. We investigated whether encapsulating TT-10 into PLGA NPs before administration could extend the duration of TT-10 delivery and improve the potency of TT-10 for treatment of MI

Methods

Results

Conclusion