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

Publication ,  Journal Article
Racioppi, L; Lento, W; Huang, W; Arvai, S; Doan, PL; Harris, JR; Marcon, F; Nakaya, HI; Liu, Y; Chao, N
Published in: Cell Death Dis
October 5, 2017

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.

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Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

October 5, 2017

Volume

8

Issue

10

Start / End Page

e3076

Location

England

Related Subject Headings

  • Whole-Body Irradiation
  • Signal Transduction
  • Regeneration
  • Radiation Injuries
  • Naphthalimides
  • Mice, Knockout
  • Mice
  • Hematopoietic Stem Cells
  • Green Fluorescent Proteins
  • Calmodulin
 

Citation

APA
Chicago
ICMJE
MLA
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Racioppi, L., Lento, W., Huang, W., Arvai, S., Doan, P. L., Harris, J. R., … Chao, N. (2017). Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis, 8(10), e3076. https://doi.org/10.1038/cddis.2017.474
Racioppi, Luigi, William Lento, Wei Huang, Stephanie Arvai, Phuong L. Doan, Jeffrey R. Harris, Fernando Marcon, Helder I. Nakaya, Yaping Liu, and Nelson Chao. “Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration.Cell Death Dis 8, no. 10 (October 5, 2017): e3076. https://doi.org/10.1038/cddis.2017.474.
Racioppi L, Lento W, Huang W, Arvai S, Doan PL, Harris JR, et al. Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis. 2017 Oct 5;8(10):e3076.
Racioppi, Luigi, et al. “Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration.Cell Death Dis, vol. 8, no. 10, Oct. 2017, p. e3076. Pubmed, doi:10.1038/cddis.2017.474.
Racioppi L, Lento W, Huang W, Arvai S, Doan PL, Harris JR, Marcon F, Nakaya HI, Liu Y, Chao N. Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis. 2017 Oct 5;8(10):e3076.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

October 5, 2017

Volume

8

Issue

10

Start / End Page

e3076

Location

England

Related Subject Headings

  • Whole-Body Irradiation
  • Signal Transduction
  • Regeneration
  • Radiation Injuries
  • Naphthalimides
  • Mice, Knockout
  • Mice
  • Hematopoietic Stem Cells
  • Green Fluorescent Proteins
  • Calmodulin