Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles

Gwang Bum Im; Yeong Hwan Kim; Yu Jin Kim; Sung Won Kim; Euiyoung Jung; Gun Jae Jeong; Ke Wang; Jinheung Kim; Dong Ik Kim; Tae Hyung Kim; Gi Ra Yi; Taekyung Yu; Suk Ho Bhang

doi:10.3390/ijms20194835

Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles

Gwang Bum Im, Yeong Hwan Kim, Yu Jin Kim, Sung Won Kim, Euiyoung Jung, Gun Jae Jeong, Ke Wang, Jinheung Kim, Dong Ik Kim, Tae Hyung Kim, Gi Ra Yi, Taekyung Yu, Suk Ho Bhang

Department of Chemistry & Nanoscience

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

18 Scopus citations

Abstract

Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as lowviability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternativemethod for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associatedwith hMSCs, a CMcan be easilymass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through thismechanism, AuFeNPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.

Original language	English
Article number	4835
Journal	International Journal of Molecular Sciences
Volume	20
Issue number	19
DOIs	https://doi.org/10.3390/ijms20194835
State	Published - 1 Oct 2019

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140).

Funding Information:
Funding: This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140).

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Angiogenesis
High passage
Mesenchymal stem cell
Nanoparticle

Access to Document

10.3390/ijms20194835

Cite this

Im, G. B., Kim, Y. H., Kim, Y. J., Kim, S. W., Jung, E., Jeong, G. J., Wang, K., Kim, J., Kim, D. I., Kim, T. H., Yi, G. R., Yu, T., & Bhang, S. H. (2019). Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles. International Journal of Molecular Sciences, 20(19), Article 4835. https://doi.org/10.3390/ijms20194835

@article{d6379d1af7a84e6399ec43fcc2dbacb1,

title = "Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles",

abstract = "Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as lowviability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternativemethod for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associatedwith hMSCs, a CMcan be easilymass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through thismechanism, AuFeNPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.",

keywords = "Angiogenesis, High passage, Mesenchymal stem cell, Nanoparticle",

author = "Im, {Gwang Bum} and Kim, {Yeong Hwan} and Kim, {Yu Jin} and Kim, {Sung Won} and Euiyoung Jung and Jeong, {Gun Jae} and Ke Wang and Jinheung Kim and Kim, {Dong Ik} and Kim, {Tae Hyung} and Yi, {Gi Ra} and Taekyung Yu and Bhang, {Suk Ho}",

note = "Funding Information: This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140). Funding Information: Funding: This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140). Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = oct,

day = "1",

doi = "10.3390/ijms20194835",

language = "English",

volume = "20",

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Im, GB, Kim, YH, Kim, YJ, Kim, SW, Jung, E, Jeong, GJ, Wang, K, Kim, J, Kim, DI, Kim, TH, Yi, GR, Yu, T & Bhang, SH 2019, 'Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles', International Journal of Molecular Sciences, vol. 20, no. 19, 4835. https://doi.org/10.3390/ijms20194835

TY - JOUR

T1 - Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles

AU - Im, Gwang Bum

AU - Kim, Yeong Hwan

AU - Kim, Yu Jin

AU - Kim, Sung Won

AU - Jung, Euiyoung

AU - Jeong, Gun Jae

AU - Wang, Ke

AU - Kim, Jinheung

AU - Kim, Dong Ik

AU - Kim, Tae Hyung

AU - Yi, Gi Ra

AU - Yu, Taekyung

AU - Bhang, Suk Ho

N1 - Funding Information: This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140). Funding Information: Funding: This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2018M3A9E2023255, NRF-2017R1A5A1070259, 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-2019R1H1A2079332, and NRF-2016M3D1A1021140). Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as lowviability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternativemethod for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associatedwith hMSCs, a CMcan be easilymass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through thismechanism, AuFeNPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.

AB - Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as lowviability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternativemethod for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associatedwith hMSCs, a CMcan be easilymass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through thismechanism, AuFeNPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.

KW - Angiogenesis

KW - High passage

KW - Mesenchymal stem cell

KW - Nanoparticle

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DO - 10.3390/ijms20194835

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VL - 20

JO - International Journal of Molecular Sciences

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M1 - 4835

ER -

Enhancing the wound healing effect of conditioned medium collected from mesenchymal stem cells with high passage number using bioreducible nanoparticles

Abstract

Bibliographical note

Keywords

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