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Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration

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(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery follo...

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Autores principales: Racioppi, Luigi, Lento, William, Huang, Wei, Arvai, Stephanie, Doan, Phuong L, Harris, Jeffrey R, Marcon, Fernando, Nakaya, Helder I, Liu, Yaping, Chao, Nelson
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680595/
https://www.ncbi.nlm.nih.gov/pubmed/28981105
http://dx.doi.org/10.1038/cddis.2017.474
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author Racioppi, Luigi
Lento, William
Huang, Wei
Arvai, Stephanie
Doan, Phuong L
Harris, Jeffrey R
Marcon, Fernando
Nakaya, Helder I
Liu, Yaping
Chao, Nelson
author_facet Racioppi, Luigi
Lento, William
Huang, Wei
Arvai, Stephanie
Doan, Phuong L
Harris, Jeffrey R
Marcon, Fernando
Nakaya, Helder I
Liu, Yaping
Chao, Nelson
author_sort Racioppi, Luigi
collection PubMed
description 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(2+)/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.
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spelling pubmed-56805952017-11-16 Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration Racioppi, Luigi Lento, William Huang, Wei Arvai, Stephanie Doan, Phuong L Harris, Jeffrey R Marcon, Fernando Nakaya, Helder I Liu, Yaping Chao, Nelson Cell Death Dis Original Article 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(2+)/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. Nature Publishing Group 2017-10 2017-10-05 /pmc/articles/PMC5680595/ /pubmed/28981105 http://dx.doi.org/10.1038/cddis.2017.474 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Racioppi, Luigi
Lento, William
Huang, Wei
Arvai, Stephanie
Doan, Phuong L
Harris, Jeffrey R
Marcon, Fernando
Nakaya, Helder I
Liu, Yaping
Chao, Nelson
Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title_full Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title_fullStr Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title_full_unstemmed Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title_short Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
title_sort calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680595/
https://www.ncbi.nlm.nih.gov/pubmed/28981105
http://dx.doi.org/10.1038/cddis.2017.474
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