Journal of Nanobiotechnology (Apr 2024)

Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct

  • Seon-Yeong Jeong,
  • Bong-Woo Park,
  • Jimin Kim,
  • Seulki Lee,
  • Haedeun You,
  • Joohyun Lee,
  • Susie Lee,
  • Jae-Hyun Park,
  • Jinju Kim,
  • Woosup Sim,
  • Kiwon Ban,
  • Joonghoon Park,
  • Hun-Jun Park,
  • Soo Kim

DOI
https://doi.org/10.1186/s12951-024-02410-x
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 20

Abstract

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Abstract Background Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. Results HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-β1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. Conclusions Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart. Graphical Abstract

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