Submitted December 7, 2007
Accepted April 18, 2008
Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors
Yu-An Cao, Amy J Wagers, Holger Karsunky, Hui Zhao, Robert Reeves, Ronald J Wong, David K Stevenson, Irving L Weissman, and Christopher H Contag*
Pediatrics, Stanford University, Palo Alto, CA, United States
Pathology, Joslin Diabetes Center, Boston, MA, United States
Stem Cell, Cellerant Therapeutics, San Carlos, CA, United States
Pathology, Stanford University, Palo Alto, CA, United States
Radiology, and Microbiology & Immunology, Stanford University, Palo Alto, CA, United States
* Corresponding author; email: ccontag{at}stanford.edu.
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 regulated by genes that mediate cellular adaptation to physiologic stress. Here we show 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.
