Endothelial cells mitigate DNA damage and promote the regeneration of hematopoietic stem cells after radiation injury.
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(+), lineage(lo), 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.
Papé Family Pediatric Research Institute, Oregon Stem Cell Center, Department of Pediatrics, Portland, OR, USA.
Derek K
DK
Zachman
Ronald P
RP
Leon
Prerna
P
Das
Devorah C
DC
Goldman
Kimberly L
KL
Hamlin
Chandan
C
Guha
William H
WH
Fleming
D000818:Animals; D001011:Aorta / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004249:DNA Damage / Q000528:radiation effects*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000528:radiation effects*; D006801:Humans; D008297:Male; D051379:Mice; D014916:Whole-Body Irradiation
D016179:Granulocyte Colony-Stimulating Factor