Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration
Abstract Background During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its pre...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-09-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13395-019-0210-5 |
| _version_ | 1818500259105472512 |
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| author | David Hardy Mylène Fefeu Aurore Besnard David Briand Paméla Gasse Fernando Arenzana-Seisdedos Pierre Rocheteau Fabrice Chrétien |
| author_facet | David Hardy Mylène Fefeu Aurore Besnard David Briand Paméla Gasse Fernando Arenzana-Seisdedos Pierre Rocheteau Fabrice Chrétien |
| author_sort | David Hardy |
| collection | DOAJ |
| description | Abstract Background During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors and by generating haptotactic gradients. Although CXCL12 has been implicated in several phases of tissue repair, the influence of GAG binding under HS influencing conditions such as acute tissue destruction remains understudied. Methods To investigate the role of the CXCL12/HS proteoglycan interactions in the pathophysiology of muscle regeneration, we performed two models of muscle injuries (notexin and freeze injury) in mutant CXCL12Gagtm/Gagtm mice, where the CXCL12 gene having been selectively mutated in critical binding sites of CXCL12 to interact with HS. Histological, cytometric, functional transcriptomic, and ultrastructure analysis focusing on the satellite cell behavior and the vessels were conducted on muscles before and after injuries. Unless specified, statistical analysis was performed with the Mann-Whitney test. Results We showed that despite normal histology of the resting muscle and normal muscle stem cell behavior in the mutant mice, endothelial cells displayed an increase in the angiogenic response in resting muscle despite the downregulated transcriptomic changes induced by the CXCL12 mutation. The regenerative capacity of the CXCL12-mutated mice was only delayed after a notexin injury, but a severe damage by freeze injury revealed a persistent defect in the muscle regeneration of CXCL12 mutant mice associated with vascular defect and fibroadipose deposition with persistent immune cell infiltration. Conclusion The present study shows that CXCL12 is crucial for proper muscle regeneration. We highlight that this homing molecule could play an important role in drastic muscle injuries and that the regeneration defect could be due to an impairment of angiogenesis, associated with a long-lasting fibro-adipogenic scar. |
| first_indexed | 2024-12-10T20:40:19Z |
| format | Article |
| id | doaj.art-a70f64a5ba594e3a8b2a790ea66a7baf |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-12-10T20:40:19Z |
| publishDate | 2019-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-a70f64a5ba594e3a8b2a790ea66a7baf2022-12-22T01:34:24ZengBMCSkeletal Muscle2044-50402019-09-019111510.1186/s13395-019-0210-5Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regenerationDavid Hardy0Mylène Fefeu1Aurore Besnard2David Briand3Paméla Gasse4Fernando Arenzana-Seisdedos5Pierre Rocheteau6Fabrice Chrétien7Experimental Neuropathology Unit, Institut PasteurExperimental Neuropathology Unit, Institut PasteurExperimental Neuropathology Unit, Institut PasteurExperimental Neuropathology Unit, Institut PasteurViral Pathogenesis Unit, Institut PasteurViral Pathogenesis Unit, Institut PasteurExperimental Neuropathology Unit, Institut PasteurExperimental Neuropathology Unit, Institut PasteurAbstract Background During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors and by generating haptotactic gradients. Although CXCL12 has been implicated in several phases of tissue repair, the influence of GAG binding under HS influencing conditions such as acute tissue destruction remains understudied. Methods To investigate the role of the CXCL12/HS proteoglycan interactions in the pathophysiology of muscle regeneration, we performed two models of muscle injuries (notexin and freeze injury) in mutant CXCL12Gagtm/Gagtm mice, where the CXCL12 gene having been selectively mutated in critical binding sites of CXCL12 to interact with HS. Histological, cytometric, functional transcriptomic, and ultrastructure analysis focusing on the satellite cell behavior and the vessels were conducted on muscles before and after injuries. Unless specified, statistical analysis was performed with the Mann-Whitney test. Results We showed that despite normal histology of the resting muscle and normal muscle stem cell behavior in the mutant mice, endothelial cells displayed an increase in the angiogenic response in resting muscle despite the downregulated transcriptomic changes induced by the CXCL12 mutation. The regenerative capacity of the CXCL12-mutated mice was only delayed after a notexin injury, but a severe damage by freeze injury revealed a persistent defect in the muscle regeneration of CXCL12 mutant mice associated with vascular defect and fibroadipose deposition with persistent immune cell infiltration. Conclusion The present study shows that CXCL12 is crucial for proper muscle regeneration. We highlight that this homing molecule could play an important role in drastic muscle injuries and that the regeneration defect could be due to an impairment of angiogenesis, associated with a long-lasting fibro-adipogenic scar.http://link.springer.com/article/10.1186/s13395-019-0210-5Muscle stem cellsEndothelial cellsCXCL12Heparan sulfatesSkeletal muscleRegeneration |
| spellingShingle | David Hardy Mylène Fefeu Aurore Besnard David Briand Paméla Gasse Fernando Arenzana-Seisdedos Pierre Rocheteau Fabrice Chrétien Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration Skeletal Muscle Muscle stem cells Endothelial cells CXCL12 Heparan sulfates Skeletal muscle Regeneration |
| title | Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration |
| title_full | Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration |
| title_fullStr | Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration |
| title_full_unstemmed | Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration |
| title_short | Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration |
| title_sort | defective angiogenesis in cxcl12 mutant mice impairs skeletal muscle regeneration |
| topic | Muscle stem cells Endothelial cells CXCL12 Heparan sulfates Skeletal muscle Regeneration |
| url | http://link.springer.com/article/10.1186/s13395-019-0210-5 |
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