KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation, marked by excessive complement activation, endothelial injury, and microangiopathy. Although complement blockade benefits some patients, effective prophylactic and therapeu...
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Ferrata Storti Foundation
2025-08-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/12207 |
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| author | Shuhui Jiang Jiaqian Qi Tingting Pan Zhenzhen Yao Siyi Lu Yifei Han Depei Wu Yue Han |
| author_facet | Shuhui Jiang Jiaqian Qi Tingting Pan Zhenzhen Yao Siyi Lu Yifei Han Depei Wu Yue Han |
| author_sort | Shuhui Jiang |
| collection | DOAJ |
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Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation, marked by excessive complement activation, endothelial injury, and microangiopathy. Although complement blockade benefits some patients, effective prophylactic and therapeutic strategies remain scarce. Therefore, plasma samples from 20 TA-TMA patients and 1:1 matched control patients (matched by age, sex, underlying diagnosis, HLA compatibility, graft source, and donor–recipient ABO blood type) were measured for krüppel-like factor 4 (KLF4), complement proteins and endothelial injury markers. The mechanism was investigated both in vitro and in vivo. In this study, plasma analysis revealed that TA-TMA patients exhibit notably lower KLF4 levels compared to matched controls, as well as elevated endothelial injury markers. In vitro, increased KLF4 expression in human umbilical vein endothelial cells significantly reduced complement deposition and mitigated endothelial damage induced by TA-TMA plasma. Furthermore, KLF4 overexpression notably decreased apoptosis and preserved endothelial barrier integrity. In a mouse model of TA-TMA triggered by dimethyloxalylglycine, upregulation of KLF4 alleviated anemia, thrombocytopenia, and renal complement deposition, while diminishing endothelial inflammatory and thrombotic markers. Intriguingly, pravastatin treatment produced similar improvements. Mechanistic analyses using CUT&Tag, RNA sequencing, luciferase assays, and quantitative real-time PCR revealed that KLF4 binds to the CD46 promoter, enhancing its transcription and thus restraining complement activation in endothelial cells. These results identify KLF4 as a key negative regulator of complement-mediated endothelial injury in TA-TMA. This conclusion is supported by CD46 knockdown abolishing KLF4-mediated benefits, highlighting the therapeutic potential of targeting KLF4 or its downstream effectors, including CD46.
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| format | Article |
| id | doaj-art-d9dad013fb914c44a9c3e4bbd1a48ec3 |
| institution | DOAJ |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Ferrata Storti Foundation |
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| series | Haematologica |
| spelling | doaj-art-d9dad013fb914c44a9c3e4bbd1a48ec32025-08-20T02:58:23ZengFerrata Storti FoundationHaematologica0390-60781592-87212025-08-01999110.3324/haematol.2025.287676KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathyShuhui Jiang0Jiaqian Qi1Tingting Pan2Zhenzhen Yao3Siyi Lu4Yifei Han5Depei Wu6Yue Han7National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, SuzhouNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Heath, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation, marked by excessive complement activation, endothelial injury, and microangiopathy. Although complement blockade benefits some patients, effective prophylactic and therapeutic strategies remain scarce. Therefore, plasma samples from 20 TA-TMA patients and 1:1 matched control patients (matched by age, sex, underlying diagnosis, HLA compatibility, graft source, and donor–recipient ABO blood type) were measured for krüppel-like factor 4 (KLF4), complement proteins and endothelial injury markers. The mechanism was investigated both in vitro and in vivo. In this study, plasma analysis revealed that TA-TMA patients exhibit notably lower KLF4 levels compared to matched controls, as well as elevated endothelial injury markers. In vitro, increased KLF4 expression in human umbilical vein endothelial cells significantly reduced complement deposition and mitigated endothelial damage induced by TA-TMA plasma. Furthermore, KLF4 overexpression notably decreased apoptosis and preserved endothelial barrier integrity. In a mouse model of TA-TMA triggered by dimethyloxalylglycine, upregulation of KLF4 alleviated anemia, thrombocytopenia, and renal complement deposition, while diminishing endothelial inflammatory and thrombotic markers. Intriguingly, pravastatin treatment produced similar improvements. Mechanistic analyses using CUT&Tag, RNA sequencing, luciferase assays, and quantitative real-time PCR revealed that KLF4 binds to the CD46 promoter, enhancing its transcription and thus restraining complement activation in endothelial cells. These results identify KLF4 as a key negative regulator of complement-mediated endothelial injury in TA-TMA. This conclusion is supported by CD46 knockdown abolishing KLF4-mediated benefits, highlighting the therapeutic potential of targeting KLF4 or its downstream effectors, including CD46. https://haematologica.org/article/view/12207 |
| spellingShingle | Shuhui Jiang Jiaqian Qi Tingting Pan Zhenzhen Yao Siyi Lu Yifei Han Depei Wu Yue Han KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy Haematologica |
| title | KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy |
| title_full | KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy |
| title_fullStr | KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy |
| title_full_unstemmed | KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy |
| title_short | KLF4 overexpression protects against complement-mediated endothelial injury in transplant-associated thrombotic microangiopathy |
| title_sort | klf4 overexpression protects against complement mediated endothelial injury in transplant associated thrombotic microangiopathy |
| url | https://haematologica.org/article/view/12207 |
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