Altered lipid metabolism promoting cardiac fibrosis is mediated by CD34+ cell-derived FABP4+ fibroblasts

纤维化 脂质代谢 心脏纤维化 细胞生物学 川地34 新陈代谢 细胞代谢 细胞 癌症研究 内科学 化学 内分泌学 医学 生物 生物化学 干细胞
作者
Luping Du,Sheng Wang,Yan Guo,Tingting Tao,Hong Wu,Xiaodong Xu,Bohuan Zhang,Ting Chen,Qingbo Xu,Xiaogang Guo
出处
期刊:Experimental and Molecular Medicine [Springer Nature]
卷期号:56 (8): 1869-1886
标识
DOI:10.1038/s12276-024-01309-9
摘要

Abstract Hyperlipidemia and hypertension might play a role in cardiac fibrosis, in which a heterogeneous population of fibroblasts seems important. However, it is unknown whether CD34 + progenitor cells are involved in the pathogenesis of heart fibrosis. This study aimed to explore the mechanism of CD34 + cell differentiation in cardiac fibrosis during hyperlipidemia. Through the analysis of transcriptomes from 50,870 single cells extracted from mouse hearts and 76,851 single cells from human hearts, we have effectively demonstrated the evolving cellular landscape throughout cardiac fibrosis. Disturbances in lipid metabolism can accelerate the development of fibrosis. Through the integration of bone marrow transplantation models and lineage tracing, our study showed that hyperlipidemia can expedite the differentiation of non-bone marrow-derived CD34+ cells into fibroblasts, particularly FABP4 + fibroblasts, in response to angiotensin II. Interestingly, the partial depletion of CD34 + cells led to a notable reduction in triglycerides in the heart, mitigated fibrosis, and improved cardiac function. Furthermore, immunostaining of human heart tissue revealed colocalization of CD34 + cells and fibroblasts. Mechanistically, our investigation of single-cell RNA sequencing data through pseudotime analysis combined with in vitro cellular studies revealed the crucial role of the PPARγ/Akt/Gsk3β pathway in orchestrating the differentiation of CD34 + cells into FABP4 + fibroblasts. Through our study, we generated valuable insights into the cellular landscape of CD34 + cell-derived cells in the hypertrophic heart with hyperlipidemia, indicating that the differentiation of non-bone marrow-derived CD34 + cells into FABP4 + fibroblasts during this process accelerates lipid accumulation and promotes heart failure via the PPARγ/Akt/Gsk3β pathway.
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