Smooth muscle-derived progenitor cell myofibroblast differentiation through KLF4 downregulation promotes arterial remodeling and fibrosis
Resident vascular adventitial SCA1+ progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage-tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA-sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling were significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM-specific expression of GLI-Kruppel family member GLI1 (Gli1), we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell-specific Kruppel-like factor 4 (Klf4) depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a profibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable antifibrotic approach.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
JCI insight - 5(2020), 23 vom: 03. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lu, Sizhao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2021 Date Revised 29.01.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.139445 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316880922 |
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| 245 | 1 | 0 | |a Smooth muscle-derived progenitor cell myofibroblast differentiation through KLF4 downregulation promotes arterial remodeling and fibrosis |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Resident vascular adventitial SCA1+ progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage-tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA-sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling were significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM-specific expression of GLI-Kruppel family member GLI1 (Gli1), we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell-specific Kruppel-like factor 4 (Klf4) depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a profibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable antifibrotic approach | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Adult stem cells | |
| 650 | 4 | |a Fibrosis | |
| 650 | 4 | |a Stem cells | |
| 650 | 4 | |a Vascular Biology | |
| 650 | 7 | |a KLF4 protein, human |2 NLM | |
| 650 | 7 | |a Klf4 protein, mouse |2 NLM | |
| 650 | 7 | |a Kruppel-Like Factor 4 |2 NLM | |
| 650 | 7 | |a Kruppel-Like Transcription Factors |2 NLM | |
| 700 | 1 | |a Jolly, Austin J |e verfasserin |4 aut | |
| 700 | 1 | |a Strand, Keith A |e verfasserin |4 aut | |
| 700 | 1 | |a Dubner, Allison M |e verfasserin |4 aut | |
| 700 | 1 | |a Mutryn, Marie F |e verfasserin |4 aut | |
| 700 | 1 | |a Moulton, Karen S |e verfasserin |4 aut | |
| 700 | 1 | |a Nemenoff, Raphael A |e verfasserin |4 aut | |
| 700 | 1 | |a Majesky, Mark W |e verfasserin |4 aut | |
| 700 | 1 | |a Weiser-Evans, Mary Cm |e verfasserin |4 aut | |
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