Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration
Abstract After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following s...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-023-00329-9 |
| _version_ | 1827635344937320448 |
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| author | Troy Anderson Julia Mo Ernesto Gagarin Desmarie Sherwood Maria Blumenkrantz Eric Mao Gianna Leon Hailey Levitz Hung-Jhen Chen Kuo-Chang Tseng Peter Fabian J. Gage Crump Joanna Smeeton |
| author_facet | Troy Anderson Julia Mo Ernesto Gagarin Desmarie Sherwood Maria Blumenkrantz Eric Mao Gianna Leon Hailey Levitz Hung-Jhen Chen Kuo-Chang Tseng Peter Fabian J. Gage Crump Joanna Smeeton |
| author_sort | Troy Anderson |
| collection | DOAJ |
| description | Abstract After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain. Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration. |
| first_indexed | 2024-03-09T15:25:28Z |
| format | Article |
| id | doaj.art-980b8a7918d740818d172734a1009a9f |
| institution | Directory Open Access Journal |
| issn | 2057-3995 |
| language | English |
| last_indexed | 2024-03-09T15:25:28Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj.art-980b8a7918d740818d172734a1009a9f2023-11-26T12:33:59ZengNature Portfolionpj Regenerative Medicine2057-39952023-09-018111510.1038/s41536-023-00329-9Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regenerationTroy Anderson0Julia Mo1Ernesto Gagarin2Desmarie Sherwood3Maria Blumenkrantz4Eric Mao5Gianna Leon6Hailey Levitz7Hung-Jhen Chen8Kuo-Chang Tseng9Peter Fabian10J. Gage Crump11Joanna Smeeton12Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaColumbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia UniversityAbstract After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain. Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration.https://doi.org/10.1038/s41536-023-00329-9 |
| spellingShingle | Troy Anderson Julia Mo Ernesto Gagarin Desmarie Sherwood Maria Blumenkrantz Eric Mao Gianna Leon Hailey Levitz Hung-Jhen Chen Kuo-Chang Tseng Peter Fabian J. Gage Crump Joanna Smeeton Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration npj Regenerative Medicine |
| title | Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration |
| title_full | Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration |
| title_fullStr | Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration |
| title_full_unstemmed | Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration |
| title_short | Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration |
| title_sort | ligament injury in adult zebrafish triggers ecm remodeling and cell dedifferentiation for scar free regeneration |
| url | https://doi.org/10.1038/s41536-023-00329-9 |
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