STAT3 Protects Hematopoietic Stem Cells by Preventing Activation of a Deleterious Autocrine Type-I Interferon Response

Authors

Bhakti Patel
Yifan Zhou
Rachel L Babcock
Feiyang Ma
M Anna Zal
Dhiraj Kumar
Yusra B Medik
Laura M Kahn
Josué E Pineda
Elizabeth M Park
Sarah M Schneider
Ximing Tang
Maria Gabriela Raso
Collene R Jeter
Tomasz Zal
Karen Clise-Dwyer
Khandan Keyomarsi
Filippo G Giancotti
Simona Colla
Stephanie S Watowich

Publication Date

5-1-2024

Journal

Leukemia

Abstract

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Keywords

Animals, STAT3 Transcription Factor, Mice, Hematopoietic Stem Cells, Interferon Type I, Autocrine Communication, Signal Transduction, Mice, Inbred C57BL, Mice, Knockout

Comments

Supplementary Material

PMID: 38467768

DOI

10.1038/s41375-024-02218-6

PMID

38467768

PMCID

PMC11283865

PubMedCentral® Posted Date

August 2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes