Transcriptomics

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STAT3 protects hematopoietic stem cells from intrinsic interferon signaling and loss of long-term blood-forming activity


ABSTRACT: The transcriptional regulator signal transducer and activator of transcription 3 (STAT3) has a well-established anti-inflammatory function in mature myeloid cells. This role, however, has precluded an understanding of STAT3 function in hematopoietic stem and progenitor cells (HSPCs), as Stat3 deletion in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. Thus, novel approaches to uncouple STAT3 function in HSPCs from the effects of systemic inflammation are needed. To address this, we established competitive mixed bone marrow (BM) chimeric mice with CreER-mediated conditional Stat3 deletion in 20% of the hematopoietic compartment. After confirming a lack of detectable inflammation in mice with Stat3-deficient BM, we found that, in contrast to Stat3-sufficient controls, Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM. Single-cell RNA sequencing of Lin-ckit+Sca1+ (LSKs) BM cells revealed an altered transcriptional landscape in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, as evidenced by the intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient LSKs accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE220466 | GEO | 2023/06/02

REPOSITORIES: GEO

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