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Theranostics 2024; 14(5):1886-1908. doi:10.7150/thno.92103 This issue Cite

Research Paper

Fibroblasts facilitate lymphatic vessel formation in transplanted heart

Hui Gong1*, Ting Wang1*, Xiaotong Sun1, Yuesheng Zhang1, Yichao Qiu2, Wenlong Sun3, Yue Zhang3, Peng Teng2, Yanhua Hu1, Xiaosheng Hu1, Liang Ma2, Qingbo Xu1, Haige Zhao2✉

1. Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. Department of Cardiovascular Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3. Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, China.
*Both authors contributed equally.

✉ Corresponding author: Haige Zhao, MD, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, Email: haigezhaoedu.cn. Or Qingbo Xu, MD, PhD, Department of Cardiology, the First Affiliated H More

Citation:
Gong H, Wang T, Sun X, Zhang Y, Qiu Y, Sun W, Zhang Y, Teng P, Hu Y, Hu X, Ma L, Xu Q, Zhao H. Fibroblasts facilitate lymphatic vessel formation in transplanted heart. Theranostics 2024; 14(5):1886-1908. doi:10.7150/thno.92103. https://www.thno.org/v14p1886.htm
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Abstract

Graphic abstract

Rationale: Lymphangiogenesis plays a critical role in the transplanted heart. The remodeling of lymphatics in the transplanted heart and the source of newly formed lymphatic vessels are still controversial, especially the mechanism of lymphangiogenesis remains limited.

Methods: Heart transplantation was performed among BALB/c, C57BL/6J, Cag-Cre, Lyve1-CreERT2;Rosa26-tdTomato and Postn(2A-CreERT2-wpre-pA)1;Rosa26-DTA mice. scRNA-seq, Elisa assay, Western blotting, Q-PCR and immunohistochemical staining were used to identify the cells and cell-cell communications of allograft heart. Cell depletion was applied to in vivo and in vitro experiments. Whole-mount staining and three-dimensional reconstruction depicted the cell distribution within transparent transplanted heart.

Results: Genetic lineage tracing mice and scRNA-seq analysis have revealed that these newly formed lymphatic vessels mainly originate from recipient LYVE1+ cells. It was found that LECs primarily interact with activated fibroblasts. Inhibition of lymphatic vessel formation using a VEGFR3 inhibitor resulted in a decreased survival time of transplanted hearts. Furthermore, when activated fibroblasts were ablated in transplanted hearts, there was a significant suppression of lymphatic vessel generation, leading to earlier graft failure. Additional investigations have shown that activated fibroblasts promote tube formation of LECs primarily through the activation of various signaling pathways, including VEGFD/VEGFR3, MDK/NCL, and SEMA3C/NRP2. Interestingly, knockdown of VEGFD and MDK in activated fibroblasts impaired cardiac lymphangiogenesis after heart transplantation.

Conclusions: Our study indicates that cardiac lymphangiogenesis primarily originates from recipient cells, and activated fibroblasts play a crucial role in facilitating the generation of lymphatic vessels after heart transplantation. These findings provide valuable insights into potential therapeutic targets for enhancing graft survival.

Keywords: heart transplantation, lymphatics, fibroblasts, cytokines, single cell RNA sequencing

Citation styles

APA
Gong, H., Wang, T., Sun, X., Zhang, Y., Qiu, Y., Sun, W., Zhang, Y., Teng, P., Hu, Y., Hu, X., Ma, L., Xu, Q., Zhao, H. (2024). Fibroblasts facilitate lymphatic vessel formation in transplanted heart. Theranostics, 14(5), 1886-1908. https://doi.org/10.7150/thno.92103.

ACS
Gong, H.; Wang, T.; Sun, X.; Zhang, Y.; Qiu, Y.; Sun, W.; Zhang, Y.; Teng, P.; Hu, Y.; Hu, X.; Ma, L.; Xu, Q.; Zhao, H. Fibroblasts facilitate lymphatic vessel formation in transplanted heart. Theranostics 2024, 14 (5), 1886-1908. DOI: 10.7150/thno.92103.

NLM
Gong H, Wang T, Sun X, Zhang Y, Qiu Y, Sun W, Zhang Y, Teng P, Hu Y, Hu X, Ma L, Xu Q, Zhao H. Fibroblasts facilitate lymphatic vessel formation in transplanted heart. Theranostics 2024; 14(5):1886-1908. doi:10.7150/thno.92103. https://www.thno.org/v14p1886.htm

CSE
Gong H, Wang T, Sun X, Zhang Y, Qiu Y, Sun W, Zhang Y, Teng P, Hu Y, Hu X, Ma L, Xu Q, Zhao H. 2024. Fibroblasts facilitate lymphatic vessel formation in transplanted heart. Theranostics. 14(5):1886-1908.

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