Cardiotrophin-Like Cytokine Factor 1 Exhibits a Myeloid-Biased Hematopoietic-Stimulating Function

Abstract

Cardiotrophin-like cytokine factor 1 (CLCF1) is secreted as a complex with the cytokine receptor-like factor 1 (CRLF1). Syndromes caused by mutations in the genes encoding CLCF1 or CRLF1 suggest an important role for CLCF1 in the development and regulation of the immune system. In mice, CLCF1 induces B-cell expansion, enhances humoral responses and triggers autoimmunity. Interestingly, inactivation of <i>CRLF1</i>, which impedes CLCF1 secretion, leads to a marked reduction in the number of bone marrow (BM) progenitor cells, while mice heterozygous for <i>CLCF1</i> display a significant decrease in their circulating leukocytes. We therefore hypothesized that CLCF1 might be implicated in the regulation of hematopoiesis. To test this hypothesis, murine hematopoietic progenitor cells defined as Lin^-Sca1⁺c-kit⁺ (LSK) were treated <i>in vitro</i> with ascending doses of CLCF1. The frequency and counts of LSK cells were significantly increased in the presence of CLCF1, which may be mediated by several CLCF1-induced soluble factors including IL-6, G-CSF, IL-1β, IL-10, and VEGF. CLCF1 administration to non-diseased C57BL/6 mice resulted in a pronounced increase in circulating myeloid cells, which was concomitant with augmented LSK and myeloid cell counts in the BM. Likewise, CLCF1 administration to mice following sub-lethal irradiation or congeneic BM transplantation (BMT) resulted in accelerated LSK recovery along with a sustained increase in BM-derived CD11b⁺ cells. Altogether, our observations establish an important and unforeseen role for CLCF1 in regulating hematopoiesis with a bias toward myeloid cell differentiation.