TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.151987 |
| _version_ | 1811226967220944896 |
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| author | Wangping Chen Danielle Pretorius Yang Zhou Yuji Nakada Jinfu Yang Jianyi Zhang |
| author_facet | Wangping Chen Danielle Pretorius Yang Zhou Yuji Nakada Jinfu Yang Jianyi Zhang |
| author_sort | Wangping Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:33:28Z |
| format | Article |
| id | doaj.art-5757b97997e84a04b40e90b1cc42617f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:33:28Z |
| publishDate | 2021-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-5757b97997e84a04b40e90b1cc42617f2022-12-22T03:38:17ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-10-01620TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarctionWangping ChenDanielle PretoriusYang ZhouYuji NakadaJinfu YangJianyi ZhangThe 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.https://doi.org/10.1172/jci.insight.151987CardiologyTherapeutics |
| spellingShingle | Wangping Chen Danielle Pretorius Yang Zhou Yuji Nakada Jinfu Yang Jianyi Zhang TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction JCI Insight Cardiology Therapeutics |
| title | TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| title_full | TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| title_fullStr | TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| title_full_unstemmed | TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| title_short | TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| title_sort | tt 10 loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction |
| topic | Cardiology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.151987 |
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