Pleiotrophin mediates hematopoietic regeneration via activation of RAS

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, PIN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PIN 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 PIN-mediated activation of RAS was dependent upon signaling through PTPRZ. PIN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PIN-mediated induction of HSC quiescence, blocked PIN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PIN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PIN to improve survival after myeloablation and suggest that PIN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.