Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport
Bone regeneration is a major clinical challenge. The main obstacles to bone injury repair are local blood flow disorders and hypoxic microenvironments. Mesenchymal stem cell (MSC) therapy has notable advantages in promoting bone-tissue regeneration. In this study, we established a mouse model of sku...
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KeAi Communications Co., Ltd.
2025-11-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25003135 |
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| author | Yitong Liu Siyan Liu Juan Du Junji Xu Jing Li Lijia Guo Yi Liu |
| author_facet | Yitong Liu Siyan Liu Juan Du Junji Xu Jing Li Lijia Guo Yi Liu |
| author_sort | Yitong Liu |
| collection | DOAJ |
| description | Bone regeneration is a major clinical challenge. The main obstacles to bone injury repair are local blood flow disorders and hypoxic microenvironments. Mesenchymal stem cell (MSC) therapy has notable advantages in promoting bone-tissue regeneration. In this study, we established a mouse model of skull bone injury treated with bone marrow mesenchymal stem cells (BMSCs). We found that local BMSC transplantation stimulated vascularized bone regeneration and matrix metalloproteinase (MMP)10 was the major regulatory protein. Local hypoxic microenvironment-induced mitochondrial permeability increased, resulting in cytoplasmic Zn2+ accumulation, which is a key factor in activating the JAK1/STAT1/MMP-10 pathway. The cytoplasmic Zn2+ enrichment caused ZRT/IRT-like protein 6 (ZIP6) inhibition was the key initiating factor in this process. Based on these findings, we designed and engineered CD90@ZIF-8-ICG, with an outer membrane chimeric CD90 antibody containing indocyanine green (ICG), to achieve increased intracellular zinc ion content by targeted delivery of the particles into local MSCs, so that local MMP-10 production and angiogenesis are regulated at the early stage of healing. ICG provided BMSCs with continuous photothermal stimulation in response to the laser intervention, which successfully achieved stable improvement of bone-defect regeneration. This study innovatively describes the regulatory importance of intracellular zinc ion homeostasis and ZIP proteins in the function of transplanted MSCs, as well as the related efficiency strategy development, which elucidates MSC therapy treatment mechanisms and provides strategies for the design and development of stem-cell-based biomaterials. |
| format | Article |
| id | doaj-art-0864de8feb7a4584be6c219504caad92 |
| institution | DOAJ |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-11-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Bioactive Materials |
| spelling | doaj-art-0864de8feb7a4584be6c219504caad922025-08-20T03:03:49ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-11-015387589210.1016/j.bioactmat.2025.07.020Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transportYitong Liu0Siyan Liu1Juan Du2Junji Xu3Jing Li4Lijia Guo5Yi Liu6Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaLaboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaLaboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaLaboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Stomatology, Huadong Hospital, Fudan University, Shanghai, China; Corresponding author.Department of Orthodontics (WangFuJing Campus), School of Stomatology, Capital Medical University, Beijing, China; Corresponding author.Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Corresponding author. Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China.Bone regeneration is a major clinical challenge. The main obstacles to bone injury repair are local blood flow disorders and hypoxic microenvironments. Mesenchymal stem cell (MSC) therapy has notable advantages in promoting bone-tissue regeneration. In this study, we established a mouse model of skull bone injury treated with bone marrow mesenchymal stem cells (BMSCs). We found that local BMSC transplantation stimulated vascularized bone regeneration and matrix metalloproteinase (MMP)10 was the major regulatory protein. Local hypoxic microenvironment-induced mitochondrial permeability increased, resulting in cytoplasmic Zn2+ accumulation, which is a key factor in activating the JAK1/STAT1/MMP-10 pathway. The cytoplasmic Zn2+ enrichment caused ZRT/IRT-like protein 6 (ZIP6) inhibition was the key initiating factor in this process. Based on these findings, we designed and engineered CD90@ZIF-8-ICG, with an outer membrane chimeric CD90 antibody containing indocyanine green (ICG), to achieve increased intracellular zinc ion content by targeted delivery of the particles into local MSCs, so that local MMP-10 production and angiogenesis are regulated at the early stage of healing. ICG provided BMSCs with continuous photothermal stimulation in response to the laser intervention, which successfully achieved stable improvement of bone-defect regeneration. This study innovatively describes the regulatory importance of intracellular zinc ion homeostasis and ZIP proteins in the function of transplanted MSCs, as well as the related efficiency strategy development, which elucidates MSC therapy treatment mechanisms and provides strategies for the design and development of stem-cell-based biomaterials.http://www.sciencedirect.com/science/article/pii/S2452199X25003135HypoxiaStem cell therapyVascularized bone regenerationZRT/IRT-Like proteinZIF-8 |
| spellingShingle | Yitong Liu Siyan Liu Juan Du Junji Xu Jing Li Lijia Guo Yi Liu Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport Bioactive Materials Hypoxia Stem cell therapy Vascularized bone regeneration ZRT/IRT-Like protein ZIF-8 |
| title | Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| title_full | Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| title_fullStr | Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| title_full_unstemmed | Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| title_short | Mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| title_sort | mechanism and regulatory strategy study on promoting vascularized bone regeneration via intracellular zinc ion transport |
| topic | Hypoxia Stem cell therapy Vascularized bone regeneration ZRT/IRT-Like protein ZIF-8 |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25003135 |
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