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Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells
Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To imp...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567771/ https://www.ncbi.nlm.nih.gov/pubmed/33064240 http://dx.doi.org/10.1186/s40580-020-00244-5 |
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author | Kim, Yeong Hwan Jung, Euiyoung Im, Gwang-Bum Kim, Yu-Jin Kim, Sung-Won Jeong, Gun-Jae Jang, Young Charles Park, Kyung Min Kim, Dong-Ik Yu, Taekyung Bhang, Suk Ho |
author_facet | Kim, Yeong Hwan Jung, Euiyoung Im, Gwang-Bum Kim, Yu-Jin Kim, Sung-Won Jeong, Gun-Jae Jang, Young Charles Park, Kyung Min Kim, Dong-Ik Yu, Taekyung Bhang, Suk Ho |
author_sort | Kim, Yeong Hwan |
collection | PubMed |
description | Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles. |
format | Online Article Text |
id | pubmed-7567771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-75677712020-10-19 Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells Kim, Yeong Hwan Jung, Euiyoung Im, Gwang-Bum Kim, Yu-Jin Kim, Sung-Won Jeong, Gun-Jae Jang, Young Charles Park, Kyung Min Kim, Dong-Ik Yu, Taekyung Bhang, Suk Ho Nano Converg Full Paper Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles. Springer Singapore 2020-10-16 /pmc/articles/PMC7567771/ /pubmed/33064240 http://dx.doi.org/10.1186/s40580-020-00244-5 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Full Paper Kim, Yeong Hwan Jung, Euiyoung Im, Gwang-Bum Kim, Yu-Jin Kim, Sung-Won Jeong, Gun-Jae Jang, Young Charles Park, Kyung Min Kim, Dong-Ik Yu, Taekyung Bhang, Suk Ho Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title | Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title_full | Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title_fullStr | Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title_full_unstemmed | Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title_short | Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
title_sort | regulation of intracellular transition metal ion level with a ph-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells |
topic | Full Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567771/ https://www.ncbi.nlm.nih.gov/pubmed/33064240 http://dx.doi.org/10.1186/s40580-020-00244-5 |
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