TY - JOUR
T1 - Endothelial cells mitigate DNA damage and promote the regeneration of hematopoietic stem cells after radiation injury
AU - Zachman, Derek K.
AU - Leon, Ronald P.
AU - Das, Prerna
AU - Goldman, Devorah C.
AU - Hamlin, Kimberly L.
AU - Guha, Chandan
AU - Fleming, William H.
N1 - Funding Information:
Special thanks to Pamela Canaday, Dorian LaTocha, and Miranda Boyd of the Flow Cytometry core at OHSU for assistance with cell sorting. Special thanks to Hyunjung Lee for technical support with housing and maintenance of mice. This work was supported by a NIH grants R01-HL069113 (W.H.F), U19-AI091175 (W.H.F., C.G.) and D.K.Z. was supported as trainee on T32-HL007781 .
PY - 2013
Y1 - 2013
N2 - Endothelial cells (ECs) are an essential component of the hematopoietic microenvironment, which maintains and regulates hematopoietic stem cells (HSCs). Although ECs can support the regeneration of otherwise lethally-irradiated HSCs, the mechanisms are not well understood. To further understand this phenomenon, we studied HSC regeneration from irradiated bone marrow using co-culture with human aortic ECs (HAECs). Co-culture with HAECs induced a 24-fold expansion of long-term HSCs (CD150+, lineagelo, Sca-1+, c-Kit+; CD150+LSK cells) in vitro. These cells gave rise to functional hematopoietic stem and progenitor cells (HSPCs) with colony-forming activity, multilineage reconstitution and serial transplantation potential. Furthermore, HAECs significantly reduced DNA damage in irradiated LSK cells within 24h. Remarkably, we were able to delay the exposure of irradiated bone marrow to the regenerative, HAEC-derived signals for up to 48h and still rescue functional HSCs. G-CSF is the gold standard for promoting hematopoietic regeneration in vivo. However, when compared to HAECs, in vitro G-CSF treatment promoted lineage differentiation and regenerated 5-fold fewer CD150+LSK cells. Together, our results show that HAECs are powerful, direct mitigators of HSC injury and DNA damage. Identification of the HAEC-derived factors that rescue HSCs may lead to improved therapies for hematopoietic regeneration after radiation injury.
AB - Endothelial cells (ECs) are an essential component of the hematopoietic microenvironment, which maintains and regulates hematopoietic stem cells (HSCs). Although ECs can support the regeneration of otherwise lethally-irradiated HSCs, the mechanisms are not well understood. To further understand this phenomenon, we studied HSC regeneration from irradiated bone marrow using co-culture with human aortic ECs (HAECs). Co-culture with HAECs induced a 24-fold expansion of long-term HSCs (CD150+, lineagelo, Sca-1+, c-Kit+; CD150+LSK cells) in vitro. These cells gave rise to functional hematopoietic stem and progenitor cells (HSPCs) with colony-forming activity, multilineage reconstitution and serial transplantation potential. Furthermore, HAECs significantly reduced DNA damage in irradiated LSK cells within 24h. Remarkably, we were able to delay the exposure of irradiated bone marrow to the regenerative, HAEC-derived signals for up to 48h and still rescue functional HSCs. G-CSF is the gold standard for promoting hematopoietic regeneration in vivo. However, when compared to HAECs, in vitro G-CSF treatment promoted lineage differentiation and regenerated 5-fold fewer CD150+LSK cells. Together, our results show that HAECs are powerful, direct mitigators of HSC injury and DNA damage. Identification of the HAEC-derived factors that rescue HSCs may lead to improved therapies for hematopoietic regeneration after radiation injury.
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U2 - 10.1016/j.scr.2013.07.001
DO - 10.1016/j.scr.2013.07.001
M3 - Article
C2 - 23939266
AN - SCOPUS:84882599171
SN - 1873-5061
VL - 11
SP - 1013
EP - 1021
JO - Stem Cell Research
JF - Stem Cell Research
IS - 3
ER -