STAT3 anti-inflammatory signaling protects hematopoietic stem cell function

Chronic inflammation damages hematopoietic stem cells (HSCs) and results in bone marrow failure, yet anti-inflammatory mechanisms that protect HSCs are understudied. The transcriptional regulator STAT3 has potent anti-inflammatory function mediated by repression of Ube2n, encoding the E2 ubiquitin-conjugating enzyme Ubc13 involved in NF-?B and MAPK activation. Here we demonstrate a crucial role for STAT3 anti-inflammatory activity in HSC preservation. Conditional Stat3 removal from hematopoietic cells results in HSC depletion, myeloid-skewed hematopoiesis and DNA damage, accompanied by intrinsic transcriptional alterations in inflammatory, survival and developmental pathways in stem and progenitor cells. Ube2n/Ubc13 deletion from Stat3-deficient hematopoietic cells corrected HSC numbers as well as aberrant hematopoietic and transcriptional responses. Collectively, our data indicate STAT3 protects HSCs from the effects of excessive pro-inflammatory signaling by modulating Ubc13.