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

doi:10.1016/j.jconrel.2020.05.038

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

Department of Chemistry & Nanoscience

Research output: Contribution to journal › Article › peer-review

19 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 language	English
Pages (from-to)	586-597
Number of pages	12
Journal	Journal of Controlled Release
Volume	324
DOIs	https://doi.org/10.1016/j.jconrel.2020.05.038
State	Published - 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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10.1016/j.jconrel.2020.05.038

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@article{b8665b34b1c144a7a4088763e9c92ef6,

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

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.",

keywords = "Angiogenesis, Cell homing, Endosome-triggered nanoparticles, Intracellular ROS control, Stem cell",

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

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: {\textcopyright} 2020",

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month = aug,

day = "10",

doi = "10.1016/j.jconrel.2020.05.038",

language = "English",

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pages = "586--597",

journal = "Journal of Controlled Release",

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T1 - Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells

AU - Im, Gwang Bum

AU - Jung, Euiyoung

AU - Kim, Yeong Hwan

AU - Kim, Yu Jin

AU - Kim, Sung Won

AU - Jeong, Gun Jae

AU - Lee, Tae Jin

AU - Kim, Dong Ik

AU - Kim, Jinheung

AU - Hyeon, Taeghwan

AU - Yu, Taekyung

AU - Bhang, Suk Ho

N1 - 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

PY - 2020/8/10

Y1 - 2020/8/10

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Cell homing

KW - Endosome-triggered nanoparticles

KW - Intracellular ROS control

KW - Stem cell

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JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -

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

Abstract

Bibliographical note

Keywords

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