TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA
Abstract Mounting evidence implicates extracellular vesicles (EVs) factors as mediators of cell therapy. Cardiosphere‐derived cells are cardiac‐derived cells with tissue reparative capacity. Activation of a downstream target of wnt/β‐catenin signalling, tryptophan 2,3 dioxygenase (TDO2) renders ther...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
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| Series: | Journal of Extracellular Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jex2.73 |
| _version_ | 1827888371395985408 |
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| author | Alessandra Ciullo Kiel Peck Xaviar Jones Shukuro Yamaguchi Ashley Anne Morris Arati Naveen Kumar Liang Li Jamie Lee Rodrigo Miguel dos Santos Eugenio Cingolani Ahmed Gamal Ibrahim |
| author_facet | Alessandra Ciullo Kiel Peck Xaviar Jones Shukuro Yamaguchi Ashley Anne Morris Arati Naveen Kumar Liang Li Jamie Lee Rodrigo Miguel dos Santos Eugenio Cingolani Ahmed Gamal Ibrahim |
| author_sort | Alessandra Ciullo |
| collection | DOAJ |
| description | Abstract Mounting evidence implicates extracellular vesicles (EVs) factors as mediators of cell therapy. Cardiosphere‐derived cells are cardiac‐derived cells with tissue reparative capacity. Activation of a downstream target of wnt/β‐catenin signalling, tryptophan 2,3 dioxygenase (TDO2) renders therapeutically inert skin fibroblasts cardioprotective. Here, we investigate the mechanism by which concentrated conditioned media from TDO2‐augmented fibroblasts (TDO2‐CCM) exert cardioprotective effects. TDO2‐CCM is cardioprotective in a mouse model of MI compared to CCM from regular fibroblasts (HDF‐CCM). Transcriptomic analysis of cardiac tissue at 24 h demonstrates broad suppression of inflammatory and cell stress markers in animals given TDO2‐CCM compared to HDF‐CCM or vehicle. Sequencing analysis of TDO2‐EV RNA demonstrated abundance of a small Y‐derived small RNA dubbed ‘NT4’. Purification of TDO2‐EVs by size‐exclusion chromatography and RNAse protection assays demonstrated that NT4 is encapsulated inside EVs. Consistently with TDO2‐CCM, macrophages exposed to NT4 showed suppression of the inflammatory and cell stress mediators, particularly p21/cdkn1a. NT4‐depleted TDO2‐CCM resulted in diminished immunomodulatory capacity. Finally, administration of NT4 alone was cardioprotective in an acute model of myocardial infarction. Taken together, these findings elucidate the mechanism by which TDO2 augmentation mediates potency in secreted EVs through enrichment of NT4 which suppresses upstream cell stress mediators including p21/cdkn1a. |
| first_indexed | 2024-03-12T20:33:43Z |
| format | Article |
| id | doaj.art-e675c2072dcb4e91b57f4a61b097a0ee |
| institution | Directory Open Access Journal |
| issn | 2768-2811 |
| language | English |
| last_indexed | 2024-03-12T20:33:43Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Biology |
| spelling | doaj.art-e675c2072dcb4e91b57f4a61b097a0ee2023-08-01T18:55:46ZengWileyJournal of Extracellular Biology2768-28112023-02-0122n/an/a10.1002/jex2.73TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNAAlessandra Ciullo0Kiel Peck1Xaviar Jones2Shukuro Yamaguchi3Ashley Anne Morris4Arati Naveen Kumar5Liang Li6Jamie Lee7Rodrigo Miguel dos Santos8Eugenio Cingolani9Ahmed Gamal Ibrahim10Smidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USASmidt Heart Institute Cedars‐Sinai Medical Center Los Angeles California USAAbstract Mounting evidence implicates extracellular vesicles (EVs) factors as mediators of cell therapy. Cardiosphere‐derived cells are cardiac‐derived cells with tissue reparative capacity. Activation of a downstream target of wnt/β‐catenin signalling, tryptophan 2,3 dioxygenase (TDO2) renders therapeutically inert skin fibroblasts cardioprotective. Here, we investigate the mechanism by which concentrated conditioned media from TDO2‐augmented fibroblasts (TDO2‐CCM) exert cardioprotective effects. TDO2‐CCM is cardioprotective in a mouse model of MI compared to CCM from regular fibroblasts (HDF‐CCM). Transcriptomic analysis of cardiac tissue at 24 h demonstrates broad suppression of inflammatory and cell stress markers in animals given TDO2‐CCM compared to HDF‐CCM or vehicle. Sequencing analysis of TDO2‐EV RNA demonstrated abundance of a small Y‐derived small RNA dubbed ‘NT4’. Purification of TDO2‐EVs by size‐exclusion chromatography and RNAse protection assays demonstrated that NT4 is encapsulated inside EVs. Consistently with TDO2‐CCM, macrophages exposed to NT4 showed suppression of the inflammatory and cell stress mediators, particularly p21/cdkn1a. NT4‐depleted TDO2‐CCM resulted in diminished immunomodulatory capacity. Finally, administration of NT4 alone was cardioprotective in an acute model of myocardial infarction. Taken together, these findings elucidate the mechanism by which TDO2 augmentation mediates potency in secreted EVs through enrichment of NT4 which suppresses upstream cell stress mediators including p21/cdkn1a.https://doi.org/10.1002/jex2.73extracellular vesiclesinflammationmacrophagesmyocardial infarctionsmall RNATDO2 |
| spellingShingle | Alessandra Ciullo Kiel Peck Xaviar Jones Shukuro Yamaguchi Ashley Anne Morris Arati Naveen Kumar Liang Li Jamie Lee Rodrigo Miguel dos Santos Eugenio Cingolani Ahmed Gamal Ibrahim TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA Journal of Extracellular Biology extracellular vesicles inflammation macrophages myocardial infarction small RNA TDO2 |
| title | TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA |
| title_full | TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA |
| title_fullStr | TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA |
| title_full_unstemmed | TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA |
| title_short | TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA |
| title_sort | tdo2 augmented fibroblasts secrete evs enriched in immunomodulatory y derived small rna |
| topic | extracellular vesicles inflammation macrophages myocardial infarction small RNA TDO2 |
| url | https://doi.org/10.1002/jex2.73 |
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