Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure
Abstract Background CD34+ cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ cell differentiation in vivo during heart failure and explore its intervention strategy. Methods We perf...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-023-03256-0 |
| _version_ | 1797865381534105600 |
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| author | Luping Du Xiaotong Sun Hui Gong Ting Wang Liujun Jiang Chengchen Huang Xiaodong Xu Zhoubin Li Hongfei Xu Liang Ma Weidong Li Ting Chen Qingbo Xu |
| author_facet | Luping Du Xiaotong Sun Hui Gong Ting Wang Liujun Jiang Chengchen Huang Xiaodong Xu Zhoubin Li Hongfei Xu Liang Ma Weidong Li Ting Chen Qingbo Xu |
| author_sort | Luping Du |
| collection | DOAJ |
| description | Abstract Background CD34+ cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ cell differentiation in vivo during heart failure and explore its intervention strategy. Methods We performed single-cell RNA sequencing (scRNA-seq) of the total non-cardiomyocytes and enriched Cd34-tdTomato+ lineage cells in the murine (male Cd34-CreERT2; Rosa26-tdTomato mice) pressure overload model (transverse aortic constriction, TAC), and total non-cardiomyocytes from human adult hearts. Then, in order to determine the origin of CD34+ cell that plays a role in myocardial fibrosis, bone marrow transplantation model was performed. Furthermore, to further clarify the role of CD34 + cells in myocardial remodeling in response to TAC injury, we generated Cd34-CreERT2; Rosa26-eGFP-DTA (Cre/DTA) mice. Results By analyzing the transcriptomes of 59,505 single cells from the mouse heart and 22,537 single cells from the human heart, we illustrated the dynamics of cell landscape during the progression of heart hypertrophy, including CD34+ cells, fibroblasts, endothelial and immune cells. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone-marrow-derived CD34+ cells give rise to fibroblasts and endothelial cells, while bone-marrow-derived CD34+ cell turned into immune cells only in response to pressure overload. Interestingly, partial depletion of CD34+ cells alleviated the severity of myocardial fibrosis with a significant improvement of cardiac function in Cd34-CreERT2; Rosa26-eGFP-DTA model. Similar changes of non-cardiomyocyte composition and cellular heterogeneity of heart failure were also observed in human patient with heart failure. Furthermore, immunostaining showed a double labeling of CD34 and fibroblast markers in human heart tissue. Mechanistically, our single-cell pseudotime analysis of scRNA-seq data and in vitro cell culture study revealed that Wnt-β-catenin and TGFβ1/Smad pathways are critical in regulating CD34+ cell differentiation toward fibroblasts. Conclusions Our study provides a cellular landscape of CD34+ cell-derived cells in the hypertrophy heart of human and animal models, indicating that non-bone-marrow-derived CD34+ cells differentiating into fibroblasts largely account for cardiac fibrosis. These findings may provide novel insights for the pathogenesis of cardiac fibrosis and have further potential therapeutic implications for the heart failure. |
| first_indexed | 2024-04-09T23:07:06Z |
| format | Article |
| id | doaj.art-1ae09bb78b0b49b983f106e15f0dee56 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-09T23:07:06Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-1ae09bb78b0b49b983f106e15f0dee562023-03-22T10:34:54ZengBMCStem Cell Research & Therapy1757-65122023-02-0114112510.1186/s13287-023-03256-0Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failureLuping Du0Xiaotong Sun1Hui Gong2Ting Wang3Liujun Jiang4Chengchen Huang5Xiaodong Xu6Zhoubin Li7Hongfei Xu8Liang Ma9Weidong Li10Ting Chen11Qingbo Xu12Department of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Lung Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Cardiovascular Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Cardiovascular Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Cardiovascular Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityDepartment of Cardiology, School of Medicine, The First Affiliated Hospital, Zhejiang UniversityAbstract Background CD34+ cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ cell differentiation in vivo during heart failure and explore its intervention strategy. Methods We performed single-cell RNA sequencing (scRNA-seq) of the total non-cardiomyocytes and enriched Cd34-tdTomato+ lineage cells in the murine (male Cd34-CreERT2; Rosa26-tdTomato mice) pressure overload model (transverse aortic constriction, TAC), and total non-cardiomyocytes from human adult hearts. Then, in order to determine the origin of CD34+ cell that plays a role in myocardial fibrosis, bone marrow transplantation model was performed. Furthermore, to further clarify the role of CD34 + cells in myocardial remodeling in response to TAC injury, we generated Cd34-CreERT2; Rosa26-eGFP-DTA (Cre/DTA) mice. Results By analyzing the transcriptomes of 59,505 single cells from the mouse heart and 22,537 single cells from the human heart, we illustrated the dynamics of cell landscape during the progression of heart hypertrophy, including CD34+ cells, fibroblasts, endothelial and immune cells. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone-marrow-derived CD34+ cells give rise to fibroblasts and endothelial cells, while bone-marrow-derived CD34+ cell turned into immune cells only in response to pressure overload. Interestingly, partial depletion of CD34+ cells alleviated the severity of myocardial fibrosis with a significant improvement of cardiac function in Cd34-CreERT2; Rosa26-eGFP-DTA model. Similar changes of non-cardiomyocyte composition and cellular heterogeneity of heart failure were also observed in human patient with heart failure. Furthermore, immunostaining showed a double labeling of CD34 and fibroblast markers in human heart tissue. Mechanistically, our single-cell pseudotime analysis of scRNA-seq data and in vitro cell culture study revealed that Wnt-β-catenin and TGFβ1/Smad pathways are critical in regulating CD34+ cell differentiation toward fibroblasts. Conclusions Our study provides a cellular landscape of CD34+ cell-derived cells in the hypertrophy heart of human and animal models, indicating that non-bone-marrow-derived CD34+ cells differentiating into fibroblasts largely account for cardiac fibrosis. These findings may provide novel insights for the pathogenesis of cardiac fibrosis and have further potential therapeutic implications for the heart failure.https://doi.org/10.1186/s13287-023-03256-0CD34+ cellsSingle-cell RNA sequencingLineage tracingMyocardial fibrosisHeart failure |
| spellingShingle | Luping Du Xiaotong Sun Hui Gong Ting Wang Liujun Jiang Chengchen Huang Xiaodong Xu Zhoubin Li Hongfei Xu Liang Ma Weidong Li Ting Chen Qingbo Xu Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure Stem Cell Research & Therapy CD34+ cells Single-cell RNA sequencing Lineage tracing Myocardial fibrosis Heart failure |
| title | Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure |
| title_full | Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure |
| title_fullStr | Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure |
| title_full_unstemmed | Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure |
| title_short | Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure |
| title_sort | single cell and lineage tracing studies reveal the impact of cd34 cells on myocardial fibrosis during heart failure |
| topic | CD34+ cells Single-cell RNA sequencing Lineage tracing Myocardial fibrosis Heart failure |
| url | https://doi.org/10.1186/s13287-023-03256-0 |
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