Cannabidiol restores hematopoietic stem cell stemness in mouse through Atf2–Lrp6 axis after acute irradiation

Bone marrow serves as the residence of hematopoietic stem cells and is recognized as one of the most radiosensitive tissues. Exposure to acute radiation leads to severe damage to bone marrow hematopoiesis which can be fatal, while few clinically applicable medication or specific therapeutic targets have been discovered. In this study, we found that the administration of cannabidiol significantly enhanced individual survival and restored the reconstitution capacity of bone marrow hematopoietic stem cells within 14 days after irradiation. Single-cell RNA sequencing analysis demonstrated that the expression levels of genes associated with stemness along with Wnt and BMP signaling pathways were restored by the cannabidiol treatment through the upregulation of <i>Atf2</i>, a transcription factor possessing multifunctional properties. <i>Atf2</i> upregulation induced by cannabidiol treatment potentially upregulated the expression of <i>Lrp6</i> to improve the stemness of hematopoietic stem cells. Further functional experiments validated the crucial role of <i>Atf2</i> in regulating multilineage differentiation potential of bone marrow hematopoietic stem and progenitor cells. Overall, our findings provide evidence for a promising radioprotective function of cannabidiol and <i>Atf2</i> as a candidate therapeutic target for acute radiation-induced hematopoietic injury, thereby paving the way for future research in the field.