PMID- 23132593
OWN - NLM
STAT- MEDLINE
DCOM- 20130718
LR  - 20220408
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 31
IP  - 2
DP  - 2013 Feb
TI  - Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell 
      regeneration following radiation injury.
PG  - 327-37
LID - 10.1002/stem.1275 [doi]
AB  - Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial 
      cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated 
      c-kit signaling. Here, we used genetic models to determine whether 
      radioprotection of BM ECs could facilitate hematopoietic regeneration following 
      radiation-induced myelosuppression. We developed mice bearing deletion of the 
      proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) 
      mice) and compared their hematopoietic recovery following total body irradiation 
      (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak 
      and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM 
      vasculature, and 100% survival following lethal dose TBI. In contrast, mice that 
      retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, 
      disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, 
      VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also 
      demonstrated increased recovery of BM stem/progenitor cells following TBI 
      compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric 
      mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed 
      significantly decreased HSC content and survival following TBI compared to mice 
      lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the 
      hematopoietic response to ionizing radiation is dependent upon HSC-autonomous 
      responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be 
      therapeutically targeted as a means to augment hematopoietic reconstitution 
      following myelosuppression.
CI  - Copyright (c) 2012 AlphaMed Press.
FAU - Doan, Phuong L
AU  - Doan PL
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, Duke University, Durham, North Carolina 27710, USA.
FAU - Russell, J Lauren
AU  - Russell JL
FAU - Himburg, Heather A
AU  - Himburg HA
FAU - Helms, Katherine
AU  - Helms K
FAU - Harris, Jeffrey R
AU  - Harris JR
FAU - Lucas, Joseph
AU  - Lucas J
FAU - Holshausen, Kirsten C
AU  - Holshausen KC
FAU - Meadows, Sarah K
AU  - Meadows SK
FAU - Daher, Pamela
AU  - Daher P
FAU - Jeffords, Laura B
AU  - Jeffords LB
FAU - Chao, Nelson J
AU  - Chao NJ
FAU - Kirsch, David G
AU  - Kirsch DG
FAU - Chute, John P
AU  - Chute JP
LA  - eng
GR  - K02 AI093866/AI/NIAID NIH HHS/United States
GR  - AI-067798-06/AI/NIAID NIH HHS/United States
GR  - T32 HL0070757-33/HL/NHLBI NIH HHS/United States
GR  - HL-086998-01/HL/NHLBI NIH HHS/United States
GR  - AI-067798-01/AI/NIAID NIH HHS/United States
GR  - U19 AI067798/AI/NIAID NIH HHS/United States
GR  - R01 HL086998/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Bak1 protein, mouse)
RN  - 0 (Bax protein, mouse)
RN  - 0 (Cadherins)
RN  - 0 (bcl-2 Homologous Antagonist-Killer Protein)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, TIE-2)
RN  - EC 2.7.10.1 (Tek protein, mouse)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/*metabolism/pathology/radiation effects
MH  - Cadherins/genetics/metabolism
MH  - Endothelial Cells/*metabolism/pathology/radiation effects
MH  - Gene Expression/radiation effects
MH  - Hematopoietic Stem Cell Transplantation
MH  - Hematopoietic Stem Cells/*metabolism/pathology/radiation effects
MH  - Mice
MH  - Mice, Transgenic
MH  - Radiation Injuries, Experimental/genetics/*metabolism/mortality/pathology
MH  - Receptor Protein-Tyrosine Kinases/*genetics/metabolism
MH  - Receptor, TIE-2
MH  - Regeneration/radiation effects
MH  - Signal Transduction/radiation effects
MH  - Survival Analysis
MH  - *Whole-Body Irradiation
MH  - bcl-2 Homologous Antagonist-Killer Protein/deficiency/genetics
MH  - bcl-2-Associated X Protein/deficiency/genetics
PMC - PMC3580267
MID - NIHMS419473
COIS- DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST: Dr. John Chute is a scientific 
      advisor to Becton Dickinson (Durham, NC).
EDAT- 2012/11/08 06:00
MHDA- 2013/07/19 06:00
PMCR- 2014/02/01
CRDT- 2012/11/08 06:00
PHST- 2012/06/05 00:00 [received]
PHST- 2012/10/06 00:00 [accepted]
PHST- 2012/11/08 06:00 [entrez]
PHST- 2012/11/08 06:00 [pubmed]
PHST- 2013/07/19 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - 10.1002/stem.1275 [doi]
PST - ppublish
SO  - Stem Cells. 2013 Feb;31(2):327-37. doi: 10.1002/stem.1275.