Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner
We previously established that vascular smooth muscle–derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not bee...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-11-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.174639 |
| _version_ | 1797634205478289408 |
|---|---|
| author | Allison M. Dubner Sizhao Lu Austin J. Jolly Keith A. Strand Marie F. Mutryn Tyler Hinthorn Tysen Noble Raphael A. Nemenoff Karen S. Moulton Mark W. Majesky Mary C.M. Weiser-Evans |
| author_facet | Allison M. Dubner Sizhao Lu Austin J. Jolly Keith A. Strand Marie F. Mutryn Tyler Hinthorn Tysen Noble Raphael A. Nemenoff Karen S. Moulton Mark W. Majesky Mary C.M. Weiser-Evans |
| author_sort | Allison M. Dubner |
| collection | DOAJ |
| description | We previously established that vascular smooth muscle–derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM cell lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM–derived cells localized throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMC), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared with WT mice. Additionally, Klf4 deletion drastically modified the phenotypes of non–AdvSca1-SM–derived cells, resulting in more contractile SMC and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potentially unstable atherosclerotic plaques. |
| first_indexed | 2024-03-11T12:05:31Z |
| format | Article |
| id | doaj.art-457a71ce90e84954826e313a6a63b0aa |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:31Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-457a71ce90e84954826e313a6a63b0aa2023-11-07T16:26:27ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01822Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent mannerAllison M. DubnerSizhao LuAustin J. JollyKeith A. StrandMarie F. MutrynTyler HinthornTysen NobleRaphael A. NemenoffKaren S. MoultonMark W. MajeskyMary C.M. Weiser-EvansWe previously established that vascular smooth muscle–derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM cell lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM–derived cells localized throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMC), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared with WT mice. Additionally, Klf4 deletion drastically modified the phenotypes of non–AdvSca1-SM–derived cells, resulting in more contractile SMC and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potentially unstable atherosclerotic plaques.https://doi.org/10.1172/jci.insight.174639Stem cellsVascular biology |
| spellingShingle | Allison M. Dubner Sizhao Lu Austin J. Jolly Keith A. Strand Marie F. Mutryn Tyler Hinthorn Tysen Noble Raphael A. Nemenoff Karen S. Moulton Mark W. Majesky Mary C.M. Weiser-Evans Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner JCI Insight Stem cells Vascular biology |
| title | Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner |
| title_full | Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner |
| title_fullStr | Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner |
| title_full_unstemmed | Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner |
| title_short | Smooth muscle–derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner |
| title_sort | smooth muscle derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a klf4 dependent manner |
| topic | Stem cells Vascular biology |
| url | https://doi.org/10.1172/jci.insight.174639 |
| work_keys_str_mv | AT allisonmdubner smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT sizhaolu smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT austinjjolly smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT keithastrand smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT mariefmutryn smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT tylerhinthorn smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT tysennoble smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT raphaelanemenoff smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT karensmoulton smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT markwmajesky smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner AT marycmweiserevans smoothmusclederivedadventitialprogenitorcellsdirectatheroscleroticplaquecompositioncomplexityinaklf4dependentmanner |