Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors.
An effective response to extreme hematopoietic stress requires an extreme elevation in hematopoiesis and preservation of hematopoietic stem cells (HSCs). These diametrically opposed processes are likely to be regulated by genes that mediate cellular adaptation to physiologic stress. Herein, we show that heme oxygenase-1 (HO-1), the inducible isozyme of heme degradation, is a key regulator of these processes. Mice lacking one allele of HO-1 (HO-1(+/-)) showed accelerated hematopoietic recovery from myelotoxic injury, and HO-1(+/-) HSCs repopulated lethally irradiated recipients with more rapid kinetics. However, HO-1(+/-) HSCs were ineffective in radioprotection and serial repopulation of myeloablated recipients. Perturbations in key stem cell regulators were observed in HO-1(+/-) HSCs and hematopoietic progenitors (HPCs), which may explain the disrupted response of HO-1(+/-) HPCs and HPCs to acute stress. Control of stem cell stress response by HO-1 presents opportunities for metabolic manipulation of stem cell-based therapies.
Cao
Yu-An
YA
Departments of Pediatrics, Stanford University School of Medicine, CA, USA.
Wagers
Amy J
AJ
Karsunky
Holger
H
Zhao
Hui
H
Reeves
Robert
R
Wong
Ronald J
RJ
Stevenson
David K
DK
Weissman
Irving L
IL
Contag
Christopher H
CH
D000220:Adaptation, Biological / Q000235:genetics*; D000465:Algorithms; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D013312:Stress, Physiological / Q000235:genetics*
D008156:Luciferases; D051547:Heme Oxygenase-1; D005472:Fluorouracil