Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells

Gwang Bum Im, Euiyoung Jung, Yeong Hwan Kim, Yu Jin Kim, Sung Won Kim, Gun Jae Jeong, Tae Jin Lee, Dong Ik Kim, Jinheung Kim, Taeghwan Hyeon, Taekyung Yu, Suk Ho Bhang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Here, we report that Fe ions delivered into human mesenchymal stem cells (hMSCs) by bioreducible metal nanoparticles (NPs) enhance their angiogenic and cell-homing efficacy by controlling ion-triggered intracellular reactive oxygen species (ROS) and improve cell migration, while reducing cytotoxicity. Endosome-triggered iron-ion-releasing nanoparticles (ETIN) were designed to be low-pH responsive to take advantage of the low-pH conditions (4–5) of endosomes for in situ iron-ion release. Due to the different redox potentials of Fe and Au, only Fe could be ionized and released from our novel ETIN, while Au remained intact after ETIN endocytosis. Treatment with an optimal amount of ETIN led to a mild increase in intracellular ROS levels in hMSCs, which enhanced the expression of HIF-1α, a key trigger for angiogenic growth factor secretion from hMSCs. Treatmetn of hMSCs with ETIN significantly enhanced the expression of angiogenesis- and lesion-targeting-related genes and proteins. Transplantation of ETIN-treated hMSCs significantly enhanced angiogenesis and tissue regeneration in a wound-closing mouse model compared with those in untreated mice and mice that underwent conventional hMSC transplantation.

Original languageEnglish
Pages (from-to)586-597
Number of pages12
JournalJournal of Controlled Release
Volume324
DOIs
StatePublished - 10 Aug 2020

Bibliographical note

Funding Information:
Kazunori Kataoka at the University of Tokyo and Kawasaki Institute of Industrial Promotion in Japan is acknowledged for his helpful advices on the manuscript development. This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT ( NRF-2018M3A9E2023255, NRF-2017R1A5A1070259 , NRF-2017R1A5A1015365 , and NRF-2019R1C1C1007384 ); by the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science , ICT and Future Planning ( NRF-2016M3A9B4919711 ) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant HI17C1728 ). This work was supported by the NRF grant funded by the Korean government (MSIP) ( NRF-2014R1A5A1009799 , NRF- 2019M3E6A1103866 , and NRF-2016M3D1A1021140 ).

Funding Information:
Kazunori Kataoka at the University of Tokyo and Kawasaki Institute of Industrial Promotion in Japan is acknowledged for his helpful advices on the manuscript development. This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, NRF-2017R1A5A1015365, and NRF-2019R1C1C1007384); by the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science, ICT and Future Planning (NRF-2016M3A9B4919711) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant HI17C1728). This work was supported by the NRF grant funded by the Korean government (MSIP) (NRF-2014R1A5A1009799, NRF- 2019M3E6A1103866, and NRF-2016M3D1A1021140).

Publisher Copyright:
© 2020

Keywords

  • Angiogenesis
  • Cell homing
  • Endosome-triggered nanoparticles
  • Intracellular ROS control
  • Stem cell

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