GSDME Knockout Alleviates Hematopoietic Stem Cell Irradiation Injury and Aggravates Myeloid-Biased Differentiation

Deguan Li ^1* Lulu Su ^2,3 Yinping Dong ¹ Bowen Guan ³ Yuquan Wang ³ Yanhua Lu ³ Xinyue Wang ¹ Wenxuan Li ¹ Qidong Huo ¹ Aimin Meng ^3*

• ¹ Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
• ² Department of Oncology, Henan Provincial Cancer Hospital, Zhengzhou, Henan Province, China
• ³ Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing Municipality, China

Bone marrow (BM) suppression is the most prevalent dose-limiting side effect of chemotherapy and radiotherapy. Exposure to ionizing radiation (IR) results in acute BM suppression and long-term BM injury. Gasdermin E (GSDME) is crucial for mediating apoptosis and pyroptosis during chemotherapy. However, its role in radiation-induced hematopoietic injury is not well established. Utilizing Gsdme -/-mice, we demonstrated that GSDME regulates the survival and differentiation of hematopoietic stem cells (HSCs). The knockout of GSDME reduced the number and proliferation of HSCs and shortened the survival time of mice post IR.Additionally, GSDME knockout protected LSK (Lin -Sca1 + c-kit + ) cells, long-term HSCs (LT-HSCs), granulocyte-monocyte progenitors (GMPs), and myeloid cells (M cells) from IR injuries during acute BM suppression. Furthermore, GSDME knockout protected LSK cells, LT-HSCs, GMPs and M cells, alleviated the proliferation inhibition of hematopoietic progenitor cells (HPCs) and exacerbated lymphocyte damage during long-term BM injury. Overall, GSDME is vital for the survival and differentiation of HSCs, and its absence promotes myeloid-biased differentiation postirradiation. These findings highlight the critical role of GSDME in radiation-induced hematopoietic injury, particularly in the myeloid differentiation of HSCs.