Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production
Background: Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by its c-terminal active globular domain (gCTRP9...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172100077X |
| _version_ | 1819291972273176576 |
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| author | Demin Liu Guoqiang Gu Lu Gan Wenjun Yan Zhen Zhang Peng Yao Di Zhu Wayne Bond Lau Dina Xie Sisi Wu Zhijun Meng Jumpei Tsukuda Theodore Christopher Bernard Lopez Jianli Zhao Erhe Gao Walter Koch Xin-Liang Ma Yajing Wang |
| author_facet | Demin Liu Guoqiang Gu Lu Gan Wenjun Yan Zhen Zhang Peng Yao Di Zhu Wayne Bond Lau Dina Xie Sisi Wu Zhijun Meng Jumpei Tsukuda Theodore Christopher Bernard Lopez Jianli Zhao Erhe Gao Walter Koch Xin-Liang Ma Yajing Wang |
| author_sort | Demin Liu |
| collection | DOAJ |
| description | Background: Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by its c-terminal active globular domain (gCTRP9). The current study attempted to: 1) identify active gCTRP9 c-terminal polypeptides with stem cell protective function; 2) determine whether a lead polypeptide may enable/enhance cortical bone-derived mesenchymal stem cell (CBSC) cardioprotection against post-myocardial infarction (post-MI) remodeling; and 3) define the responsible underlying cellular/molecular mechanisms. Methods and results: Utilizing I-TASSER structure prediction and 3-D active site modeling, we cloned and purified 3 gCTRP9 fragments (CTRP9-237, CTRP9-277, and CTRP9-281). Their activation of cell salvage kinase was compared against gCTRP9. Among the three fragments, CTRP9-281 (a 45 residue-containing polypeptide) exerted comparable or greater ERK1/2 activation compared to gCTRP9. Treatment with CTRP9-281 or gCTRP9 significantly increased CBSC proliferation and migration, and attenuated oxidative stress-induced CBSC apoptosis. CTRP9-281 and gCTRP9 comparably upregulated SOD2 and SOD3 expression. However, CTRP9-281, not gCTRP9, upregulated FGF2 and VEGFA expression/secretion in an ERK1/2 dependent manner. Administration of gCTRP9 or CTRP9-281 alone attenuated post-MI cardiac dysfunction and improved CBSC retention in the infarcted heart in similar fashion. However, CTRP9-281 exerted greater synergistic effect with CBSC than gCTRP9 related to pro-angiogenic, anti-fibrotic, and anti-remodeling effects. Mechanistically, CTRP9-281 significantly increased SOD2-rich and VEGFA-rich exosome production by CBSC. Exosomes from CTRP9-281 treated CBSC significantly attenuated oxidative stress-induced cardiomyocyte apoptosis in vitro. An exosome generation inhibitor attenuated CTRP9-281 enhancement of CBSC cardioprotection in vivo. Conclusion: We identified a CTRP9 polypeptide that upregulates SOD2/SOD3 expression and improves CBSC survival/retention, similar to gCTRP9. Moreover, CTRP9-281 stimulates VEGFA-rich exosome production by CBSC, exerting superior pro-angiogenic, anti-fibrotic, and cardioprotective actions. |
| first_indexed | 2024-12-24T03:47:07Z |
| format | Article |
| id | doaj.art-c9de3c2bfe2b42b4af376507cce90d13 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-24T03:47:07Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-c9de3c2bfe2b42b4af376507cce90d132022-12-21T17:16:41ZengElsevierRedox Biology2213-23172021-05-0141101929Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome productionDemin Liu0Guoqiang Gu1Lu Gan2Wenjun Yan3Zhen Zhang4Peng Yao5Di Zhu6Wayne Bond Lau7Dina Xie8Sisi Wu9Zhijun Meng10Jumpei Tsukuda11Theodore Christopher12Bernard Lopez13Jianli Zhao14Erhe Gao15Walter Koch16Xin-Liang Ma17Yajing Wang18Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USACenter for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USADepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA; Corresponding author. Department of Emergency Medicine and Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA; Corresponding author.Background: Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by its c-terminal active globular domain (gCTRP9). The current study attempted to: 1) identify active gCTRP9 c-terminal polypeptides with stem cell protective function; 2) determine whether a lead polypeptide may enable/enhance cortical bone-derived mesenchymal stem cell (CBSC) cardioprotection against post-myocardial infarction (post-MI) remodeling; and 3) define the responsible underlying cellular/molecular mechanisms. Methods and results: Utilizing I-TASSER structure prediction and 3-D active site modeling, we cloned and purified 3 gCTRP9 fragments (CTRP9-237, CTRP9-277, and CTRP9-281). Their activation of cell salvage kinase was compared against gCTRP9. Among the three fragments, CTRP9-281 (a 45 residue-containing polypeptide) exerted comparable or greater ERK1/2 activation compared to gCTRP9. Treatment with CTRP9-281 or gCTRP9 significantly increased CBSC proliferation and migration, and attenuated oxidative stress-induced CBSC apoptosis. CTRP9-281 and gCTRP9 comparably upregulated SOD2 and SOD3 expression. However, CTRP9-281, not gCTRP9, upregulated FGF2 and VEGFA expression/secretion in an ERK1/2 dependent manner. Administration of gCTRP9 or CTRP9-281 alone attenuated post-MI cardiac dysfunction and improved CBSC retention in the infarcted heart in similar fashion. However, CTRP9-281 exerted greater synergistic effect with CBSC than gCTRP9 related to pro-angiogenic, anti-fibrotic, and anti-remodeling effects. Mechanistically, CTRP9-281 significantly increased SOD2-rich and VEGFA-rich exosome production by CBSC. Exosomes from CTRP9-281 treated CBSC significantly attenuated oxidative stress-induced cardiomyocyte apoptosis in vitro. An exosome generation inhibitor attenuated CTRP9-281 enhancement of CBSC cardioprotection in vivo. Conclusion: We identified a CTRP9 polypeptide that upregulates SOD2/SOD3 expression and improves CBSC survival/retention, similar to gCTRP9. Moreover, CTRP9-281 stimulates VEGFA-rich exosome production by CBSC, exerting superior pro-angiogenic, anti-fibrotic, and cardioprotective actions.http://www.sciencedirect.com/science/article/pii/S221323172100077XCardiokineCell therapyExosomePathological cardiac remodeling |
| spellingShingle | Demin Liu Guoqiang Gu Lu Gan Wenjun Yan Zhen Zhang Peng Yao Di Zhu Wayne Bond Lau Dina Xie Sisi Wu Zhijun Meng Jumpei Tsukuda Theodore Christopher Bernard Lopez Jianli Zhao Erhe Gao Walter Koch Xin-Liang Ma Yajing Wang Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production Redox Biology Cardiokine Cell therapy Exosome Pathological cardiac remodeling |
| title | Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| title_full | Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| title_fullStr | Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| title_full_unstemmed | Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| title_short | Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| title_sort | identification of a ctrp9 c terminal polypeptide capable of enhancing bone derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production |
| topic | Cardiokine Cell therapy Exosome Pathological cardiac remodeling |
| url | http://www.sciencedirect.com/science/article/pii/S221323172100077X |
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