Table_1_Rheb1-Deficient Neutrophils Promote Hematopoietic Stem/Progenitor Cell Proliferation via Mesenchymal Stem Cells.DOCX

Myeloid cells have been identified as hematopoietic stem cell (HSC)-regulating cells. However, the mechanisms by which myeloid cells regulate the function of HSCs are not fully defined. Our previous study indicated that the HSCs are over-expanded in Vav1-Cre;Rheb1fl/fl mice. Here, using in vivo and in vitro models, we found that Rheb1-deficient neutrophils remodeled the bone marrow environment and induced expansion of HSCs in vivo. Further studies showed that loss of Rheb1 impaired neutrophils’ ability to secrete IL-6, led mesenchymal stem cells (MSCs) to produce more SCF, and promote HSC proliferation. We further found that IL-6 suppressed SCF mRNA expression in human MSCs. Interesting, the high level of IL-6 was also related with poor survival of chronic myeloid leukemia (CML) patients, and higher expression of IL-6 in CML cells is associated with the lower expression of SCF in MSCs in patients. Our studies suggested that blocking IL-6 signaling pathway might stimulate MSCs to secrete more SCF, and to support hematopoietic stem/progenitor cells proliferation.

髓系细胞已被鉴定为造血干细胞（hematopoietic stem cell, HSC）的调控细胞。然而，髓系细胞调控造血干细胞功能的具体机制尚未完全明确。我们前期研究发现，Vav1-Cre;Rheb1fl/fl小鼠体内的造血干细胞出现过度扩增现象。本研究通过体内（in vivo）与体外（in vitro）模型开展实验，发现Rheb1缺陷型中性粒细胞可重塑骨髓微环境，并在体内诱导造血干细胞扩增。进一步研究表明，Rheb1缺失会削弱中性粒细胞分泌白细胞介素6（Interleukin 6, IL-6）的能力，促使间充质干细胞（mesenchymal stem cells, MSCs）分泌更多干细胞因子（Stem Cell Factor, SCF），进而促进造血干细胞增殖。我们进一步发现，白细胞介素6会抑制人源间充质干细胞中干细胞因子的mRNA表达。值得注意的是，高水平的白细胞介素6与慢性髓系白血病（chronic myeloid leukemia, CML）患者的不良生存期相关，且患者体内慢性髓系白血病细胞中白细胞介素6的高表达，与间充质干细胞中干细胞因子的低表达存在关联。本研究提示，阻断白细胞介素6信号通路或许可刺激间充质干细胞分泌更多干细胞因子，从而支持造血干/祖细胞的增殖。