Abstract
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 Ca2+/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.
Highlights
Hematopoietic stem and progenitor cells (HSPCs) reside in specialized bone marrow (BM) niches that provide signals to ensure blood production and maintain the long-term hematopoietic stem cell (LT-HSC) pool
We examined the in vivo sensitivity of HSPC to radiation-induced apoptosis to determine the cellular basis of the accelerated hematopoietic recovery in Camkk[2] null mice
Our results uncover an important role for CaMKK2 in the mechanism controlling HSPC regeneration
Summary
Hematopoietic stem and progenitor cells (HSPCs) reside in specialized bone marrow (BM) niches that provide signals to ensure blood production and maintain the long-term hematopoietic stem cell (LT-HSC) pool. Extensive studies of the niche have identified several cell types such as osteoblasts,[1] endothelial cells,[2] osteomacs,[3] regulatory T cells[4] and sympathetic neurons[5] as contributors of the physiologic microenvironment.[6,7] These cells engage HSPC through both physical contacts and soluble paracrine signaling molecules including CXC chemokine ligand 12 (CXCL12), stem cell factor (SCF), non-canonical and canonical Wnt ligands, and epidermal growth factor[8,9] to control niche retention and selfrenewal These molecules may trigger calcium transients, the role of calcium-dependent cascades in the mechanism regulating HSCP regeneration has not been elucidated.[10,11,12,13]. The transient inhibition of CaMKK2 with the small molecule CaMKK2 kinase inhibitor STO-60920 improves survival and hematopoietic regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
