Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells
The technology of induced pluripotent stem cells (iPSCs) has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming. This approach provides possibilities for cell replacement therapies and drug screening, but the potential risk of tumorigenesis hampers its fu...
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KeAi Communications Co., Ltd.
2025-03-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X24005024 |
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| author | Peng Tang Fuxiang Wei Weihua Qiao Xing Chen Chenyang Ji Wanzhi Yang Xinyu Zhang Sihan Chen Yanyan Wu Mingxing Jiang Chenyu Ma Weiqiang Shen Qi Dong Hong Cao Minghui Xie Ziwen Cai Li Xu Jiawei Shi Nianguo Dong Junwei Chen Ning Wang |
| author_facet | Peng Tang Fuxiang Wei Weihua Qiao Xing Chen Chenyang Ji Wanzhi Yang Xinyu Zhang Sihan Chen Yanyan Wu Mingxing Jiang Chenyu Ma Weiqiang Shen Qi Dong Hong Cao Minghui Xie Ziwen Cai Li Xu Jiawei Shi Nianguo Dong Junwei Chen Ning Wang |
| author_sort | Peng Tang |
| collection | DOAJ |
| description | The technology of induced pluripotent stem cells (iPSCs) has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming. This approach provides possibilities for cell replacement therapies and drug screening, but the potential risk of tumorigenesis hampers its further development and in vivo application. How to generate differentiated cells such as valvular endothelial cells (VECs) has remained a major challenge.Utilizing a combinatorial strategy of selective soluble chemicals, cytokines and substrate stiffness modulation, mouse embryonic fibroblasts are directly and efficiently transdifferentiated into induced aortic endothelial cell-like cells (iAECs), or human primary adult fibroblasts are transdifferentiated into induced valvular endothelial cell-like cells (hiVECs), without expressing pluripotency stem cell markers. These iAECs and hiVECs express VEC-associated genes and proteins and VEC-specific marker NFATC1 and are functional in culture and on decellularized porcine aortic valves, like mouse aortic endothelial cells or human primary aortic valvular endothelial cells. The iAECs and hiVECs seeded on decellularized porcine aortic valves stay intact and express VEC-associated proteins for 60 days after grafting into abdominal aorta of immune-compromised rats. In contrast, induced pluripotent stem cells (iPSCs) are less efficient in differentiating into VEC-like cells and pluripotency marker Nanog is expressed in a small subpopulation of iPSC-derived VEC-like cells that generate teratomas in SCID mice whereas hiVECs derived from transdifferentiation do not generate teratomas in vivo. Our findings highlight an approach to efficiently convert fibroblasts into iAECs and hiVECs and seed them onto decellularized aortic valves for safely generating autologous tissue-engineered aortic valves without using viruses or first reprogramming the cells into pluripotent stem cells. |
| format | Article |
| id | doaj-art-23e0d4add2654c4e8b19d30c02d1fd2b |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-23e0d4add2654c4e8b19d30c02d1fd2b2025-01-26T05:04:22ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-03-0145181200Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cellsPeng Tang0Fuxiang Wei1Weihua Qiao2Xing Chen3Chenyang Ji4Wanzhi Yang5Xinyu Zhang6Sihan Chen7Yanyan Wu8Mingxing Jiang9Chenyu Ma10Weiqiang Shen11Qi Dong12Hong Cao13Minghui Xie14Ziwen Cai15Li Xu16Jiawei Shi17Nianguo Dong18Junwei Chen19Ning Wang20Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author.Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China; Corresponding author.Institute for Mechanobiology, Department of Bioengineering, College of Engineering, Northeastern University, Boston, MA, 02115, USA; Corresponding author.The technology of induced pluripotent stem cells (iPSCs) has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming. This approach provides possibilities for cell replacement therapies and drug screening, but the potential risk of tumorigenesis hampers its further development and in vivo application. How to generate differentiated cells such as valvular endothelial cells (VECs) has remained a major challenge.Utilizing a combinatorial strategy of selective soluble chemicals, cytokines and substrate stiffness modulation, mouse embryonic fibroblasts are directly and efficiently transdifferentiated into induced aortic endothelial cell-like cells (iAECs), or human primary adult fibroblasts are transdifferentiated into induced valvular endothelial cell-like cells (hiVECs), without expressing pluripotency stem cell markers. These iAECs and hiVECs express VEC-associated genes and proteins and VEC-specific marker NFATC1 and are functional in culture and on decellularized porcine aortic valves, like mouse aortic endothelial cells or human primary aortic valvular endothelial cells. The iAECs and hiVECs seeded on decellularized porcine aortic valves stay intact and express VEC-associated proteins for 60 days after grafting into abdominal aorta of immune-compromised rats. In contrast, induced pluripotent stem cells (iPSCs) are less efficient in differentiating into VEC-like cells and pluripotency marker Nanog is expressed in a small subpopulation of iPSC-derived VEC-like cells that generate teratomas in SCID mice whereas hiVECs derived from transdifferentiation do not generate teratomas in vivo. Our findings highlight an approach to efficiently convert fibroblasts into iAECs and hiVECs and seed them onto decellularized aortic valves for safely generating autologous tissue-engineered aortic valves without using viruses or first reprogramming the cells into pluripotent stem cells.http://www.sciencedirect.com/science/article/pii/S2452199X24005024TransdifferentiationValvular endothelial cellsTissue engineered aortic valvesSoluble factors, Substrate stiffness |
| spellingShingle | Peng Tang Fuxiang Wei Weihua Qiao Xing Chen Chenyang Ji Wanzhi Yang Xinyu Zhang Sihan Chen Yanyan Wu Mingxing Jiang Chenyu Ma Weiqiang Shen Qi Dong Hong Cao Minghui Xie Ziwen Cai Li Xu Jiawei Shi Nianguo Dong Junwei Chen Ning Wang Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells Bioactive Materials Transdifferentiation Valvular endothelial cells Tissue engineered aortic valves Soluble factors, Substrate stiffness |
| title | Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells |
| title_full | Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells |
| title_fullStr | Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells |
| title_full_unstemmed | Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells |
| title_short | Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells |
| title_sort | engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or ips cells |
| topic | Transdifferentiation Valvular endothelial cells Tissue engineered aortic valves Soluble factors, Substrate stiffness |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X24005024 |
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