{"title":"CD34+ 细胞移植通过先天免疫调节减轻代谢功能障碍相关性脂肪性肝炎小鼠的纤维化肝损伤","authors":"","doi":"10.1016/j.jcyt.2024.03.488","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34<sup>+</sup> cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34<sup>+</sup> cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of <em>ex vivo</em>-expanded CD34<sup>+</sup> cells in treating MASH livers.</p></div><div><h3>Materials and methods</h3><p>Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34<sup>+</sup> cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation.</p></div><div><h3>Results</h3><p>Expanded CD34<sup>+</sup> cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of <em>Col1a1</em> and <em>Timp1</em>. Furthermore, engrafted CD34<sup>+</sup> cells reduced alanine transaminase levels, the number of TUNEL<sup>+</sup> hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that \"defense response to virus\" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of <em>RIG-I-like receptors/Irf7/Stat1/Cxcl10</em> axis in expanded CD34<sup>+</sup> cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver.</p></div><div><h3>Conclusions</h3><p>These findings suggest that transplanted expanded CD34<sup>+</sup> cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.</p></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ex-vivo expanded CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice\",\"authors\":\"\",\"doi\":\"10.1016/j.jcyt.2024.03.488\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34<sup>+</sup> cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34<sup>+</sup> cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of <em>ex vivo</em>-expanded CD34<sup>+</sup> cells in treating MASH livers.</p></div><div><h3>Materials and methods</h3><p>Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34<sup>+</sup> cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation.</p></div><div><h3>Results</h3><p>Expanded CD34<sup>+</sup> cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of <em>Col1a1</em> and <em>Timp1</em>. Furthermore, engrafted CD34<sup>+</sup> cells reduced alanine transaminase levels, the number of TUNEL<sup>+</sup> hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that \\\"defense response to virus\\\" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of <em>RIG-I-like receptors/Irf7/Stat1/Cxcl10</em> axis in expanded CD34<sup>+</sup> cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver.</p></div><div><h3>Conclusions</h3><p>These findings suggest that transplanted expanded CD34<sup>+</sup> cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.</p></div>\",\"PeriodicalId\":50597,\"journal\":{\"name\":\"Cytotherapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cytotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1465324924005802\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cytotherapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1465324924005802","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Ex-vivo expanded CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice
Background
In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating MASH livers.
Materials and methods
Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation.
Results
Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver.
Conclusions
These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.
期刊介绍:
The journal brings readers the latest developments in the fast moving field of cellular therapy in man. This includes cell therapy for cancer, immune disorders, inherited diseases, tissue repair and regenerative medicine. The journal covers the science, translational development and treatment with variety of cell types including hematopoietic stem cells, immune cells (dendritic cells, NK, cells, T cells, antigen presenting cells) mesenchymal stromal cells, adipose cells, nerve, muscle, vascular and endothelial cells, and induced pluripotential stem cells. We also welcome manuscripts on subcellular derivatives such as exosomes. A specific focus is on translational research that brings cell therapy to the clinic. Cytotherapy publishes original papers, reviews, position papers editorials, commentaries and letters to the editor. We welcome "Protocols in Cytotherapy" bringing standard operating procedure for production specific cell types for clinical use within the reach of the readership.