Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest 2014 Nov;124(11):4753-8
Date
09/25/2014Pubmed ID
25250571Pubmed Central ID
PMC4347246DOI
10.1172/JCI76838Scopus ID
2-s2.0-84908636760 33 CitationsAbstract
Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.
Author List
Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W, Chao NJ, Slamon DJ, Chute JPAuthor
Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Marrow Transplantation
Carrier Proteins
Cells, Cultured
Cytokines
Hematopoiesis
Mice
Radiation Injuries, Experimental
Regeneration
Signal Transduction
ras Proteins
