Chung Yang-Jo, Park Bo-Bae, Kang Young-Ju, Kim Tae-Min, Eaves Connie J, Oh Il-Hoan
Catholic Cell Therapy Center, Catholic University of Korea School of Medicine, Seocho-Ku, Seoul, Korea.
Blood. 2006 Aug 15;108(4):1208-15. doi: 10.1182/blood-2006-01-010199. Epub 2006 Apr 13.
Self-renewal of hematopoietic stem cells (HSCs) is key to their reconstituting ability, but the signaling pathways that regulate this process remain poorly understood. Here we show that transduction of adult mouse bone marrow cells with a constitutively activated form of Stat3 (Stat3-C) increased their regenerative activity in lethally irradiated recipients. Conversely, transduction of these cells with a dominant-negative form of Stat3 suppressed their regenerative activity. Serial transplantation and clonal tracking of the HSC progeny regenerated in vivo from STAT3-C-transduced HSCs demonstrated that the major effect of forced expression of STAT3-C was to enhance HSC self-renewal during the initial phase of hematopoietic recovery. This acquired potential for enhanced self-renewal divisions then became latent, but was reactivated when the cells were transferred to new irradiated recipients. Increased levels of activated STAT3 were also found to be associated with greater preservation of primitive hematopoietic cells in short-term cultures. These results indicate a novel biphasic regulation of HSC self-renewal in vivo in which activated STAT3 promotes HSC self-renewal under stimulated, but not homeostatic, conditions. STAT3 may thus be an important regulator of hematopoietic regeneration and a novel target for HSC engineering.
造血干细胞（HSC）的自我更新是其重建能力的关键，但调节这一过程的信号通路仍知之甚少。我们在此表明，用组成型激活形式的Stat3（Stat3-C）转导成年小鼠骨髓细胞可增加其在接受致死性照射的受体中的再生活性。相反，用显性负性形式的Stat3转导这些细胞会抑制其再生活性。对从STAT3-C转导的HSC体内再生的HSC后代进行连续移植和克隆追踪表明，强制表达STAT3-C的主要作用是在造血恢复的初始阶段增强HSC的自我更新。这种增强自我更新分裂的获得性潜能随后变得潜伏，但当细胞转移到新的受照射受体时会重新激活。还发现激活的STAT3水平升高与短期培养中原始造血细胞的更好保存有关。这些结果表明，体内HSC自我更新存在一种新的双相调节，其中激活的STAT3在受刺激而非稳态条件下促进HSC自我更新。因此，STAT3可能是造血再生的重要调节因子，也是HSC工程的新靶点。
