APEX1 nuclease and redox functions are both essential for adult mouse hematopoietic stem and progenitor cells.

ABSTRACT: Self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) is carefully controlled by extrinsic and intrinsic factors, to ensure the lifelong process of hematopoiesis. Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein implicated in DNA repair and transcriptional regulation. Although previous studies have emphasized the necessity of studying APEX1 in lineage-specific context and its role in some progenitor cells, no studies have assessed the role of APEX1, nor its two enzymatic domains, in supporting adult HSPC function. In this study, we demonstrated that complete loss of APEX1 from murine bone marrow HSPCs (induced by CRSIPR/Cas9) caused severe hematopoietic failure following transplantation, as well as an ex vivo HSPC expansion defect. Using specific inhibitors against either the nuclease or redox domains of APEX1 in combination with single cell transcriptomics (CITE-seq), we found that both APEX1 nuclease and redox domains are regulating mouse ex vivo HSPC proliferation, differentiation and survival, but through distinct mechanisms. Inhibition of the APEX1 nuclease function resulted in loss of HSPCs accompanied by early activation of differentiation programs and enhanced lineage commitment. By contrast, inhibition of the APEX1 redox function significantly downregulated interferon signaling in expanding HSPCs and their progeny, resulting in dysfunctional megakaryocyte-biased HSPCs, loss of monocytes and lymphoid progenitor cells. In conclusion, we demonstrate that APEX1 is a key regulator for adult regenerative hematopoiesis, and that the APEX1 nuclease and redox domains differentially impact lineage specification and stemness of functional ex vivo cultured HSPCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE218981 | GEO | 2023/06/02

REPOSITORIES: GEO