Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy
Abstract Background Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynam...
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| Format: | Article |
| Language: | English |
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BMC
2025-03-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04164-1 |
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| author | Ming-Min Chang Dinh Toi Chu Sheng-Che Lin Jung-Shun Lee Thuy Duong Vu Hue Thi Vu Thamil Selvee Ramasamy Shau-Ping Lin Chia-Ching Wu |
| author_facet | Ming-Min Chang Dinh Toi Chu Sheng-Che Lin Jung-Shun Lee Thuy Duong Vu Hue Thi Vu Thamil Selvee Ramasamy Shau-Ping Lin Chia-Ching Wu |
| author_sort | Ming-Min Chang |
| collection | DOAJ |
| description | Abstract Background Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency. Methods ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation. Results Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery. Conclusion Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications. |
| format | Article |
| id | doaj-art-f68c6e95433e4d5f8976cd7aa61d8f30 |
| institution | DOAJ |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-f68c6e95433e4d5f8976cd7aa61d8f302025-08-20T02:56:16ZengBMCStem Cell Research & Therapy1757-65122025-03-0116112110.1186/s13287-025-04164-1Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapyMing-Min Chang0Dinh Toi Chu1Sheng-Che Lin2Jung-Shun Lee3Thuy Duong Vu4Hue Thi Vu5Thamil Selvee Ramasamy6Shau-Ping Lin7Chia-Ching Wu8Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung UniversityFaculty of Applied Sciences, International School, Vietnam National UniversityDivision of Plastic and Reconstructive Surgery, Tainan Municipal An-Nan Hospital-China Medical UniversityDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung UniversityFaculty of Applied Sciences, International School, Vietnam National UniversityFaculty of Applied Sciences, International School, Vietnam National UniversityStem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of MalayaInstitute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan UniversityDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung UniversityAbstract Background Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency. Methods ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation. Results Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery. Conclusion Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.https://doi.org/10.1186/s13287-025-04164-1Enhanced mitochondrial functionAdipose-derived stem cells3D spheroid cultureChitosan nano-depositionEZH2-H3K27me3-PPARγ pathwayMitochondrial therapy |
| spellingShingle | Ming-Min Chang Dinh Toi Chu Sheng-Che Lin Jung-Shun Lee Thuy Duong Vu Hue Thi Vu Thamil Selvee Ramasamy Shau-Ping Lin Chia-Ching Wu Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy Stem Cell Research & Therapy Enhanced mitochondrial function Adipose-derived stem cells 3D spheroid culture Chitosan nano-deposition EZH2-H3K27me3-PPARγ pathway Mitochondrial therapy |
| title | Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy |
| title_full | Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy |
| title_fullStr | Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy |
| title_full_unstemmed | Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy |
| title_short | Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy |
| title_sort | enhanced mitochondrial function and delivery from adipose derived stem cell spheres via the ezh2 h3k27me3 pparγ pathway for advanced therapy |
| topic | Enhanced mitochondrial function Adipose-derived stem cells 3D spheroid culture Chitosan nano-deposition EZH2-H3K27me3-PPARγ pathway Mitochondrial therapy |
| url | https://doi.org/10.1186/s13287-025-04164-1 |
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