Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Cell Death Dis. 2017 Oct 5;8(10):e3076. doi: 10.1038/cddis.2017.474.
Hematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature. Accordingly, HSPC from Camkk2 null mice have a high proliferative capability when stimulated in vitro in the presence of BM-derived endothelial cells. In addition, Camkk2 null mice are more resistant to radiation injury and show accelerated hematopoietic recovery, enhanced HSPC regeneration and ultimately a prolonged survival following sublethal or lethal total body irradiation. Mechanistically, we propose that CaMKK2 regulates the HSPC response to hematopoietic damage by coupling radiation signaling to activation of the anti-proliferative AMP-activated protein kinase. Finally, we demonstrated that systemic administration of the small molecule CaMKK2 inhibitor, STO-609, to irradiated mice enhanced HSPC recovery and improved survival. These findings identify CaMKK2 as an important regulator of HSPC regeneration and demonstrate CaMKK2 inhibition is a novel approach to promoting hematopoietic recovery after BM injury.
造血干/祖细胞（HSPCs）在成人体内主要处于静止状态，但在骨髓（BM）损伤时会增殖。在这里，我们表明钙/钙调蛋白（CaM）依赖性蛋白激酶激酶 2（CaMKK2）的缺失促进了 HSPC 再生和辐射损伤后的造血恢复。使用 Camkk2 增强型绿色荧光蛋白（EGFP）报告小鼠，我们发现 Camkk2 表达在 HSPC 中呈发育调节。HSPC 中 Camkk2 的缺失导致与静止特征相关的基因显著下调。因此，当在存在 BM 衍生的内皮细胞的情况下在体外刺激时，Camkk2 缺失的 HSPC 具有高增殖能力。此外，Camkk2 缺失的小鼠对辐射损伤更具抵抗力，并表现出加速的造血恢复、增强的 HSPC 再生，最终在亚致死或致死全身照射后延长存活时间。从机制上讲，我们提出 CaMKK2 通过将辐射信号与抗增殖的 AMP 激活蛋白激酶的激活偶联，调节 HSPC 对造血损伤的反应。最后，我们证明了向辐照小鼠系统给予小分子 CaMKK2 抑制剂 STO-609 可增强 HSPC 恢复并提高存活率。这些发现确定了 CaMKK2 是 HSPC 再生的重要调节剂，并证明了 CaMKK2 抑制是促进 BM 损伤后造血恢复的新方法。
