Pleiotrophin mediates hematopoietic regeneration via activation of RAS
Heather A. Himburg, … , Dennis J. Slamon, John P. Chute
Heather A. Himburg, … , Dennis J. Slamon, John P. Chute
Published September 24, 2014
Citation Information: J Clin Invest. 2014;124(11):4753-4758. https://doi.org/10.1172/JCI76838.
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Brief Report Hematology

Pleiotrophin mediates hematopoietic regeneration via activation of RAS

Abstract

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.

Authors

Heather A. Himburg, Xiao Yan, Phuong L. Doan, Mamle Quarmyne, Eva Micewicz, William McBride, Nelson J. Chao, Dennis J. Slamon, John P. Chute

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Figure 1

PTN treatment improves the survival of irradiated mice and hematopoietic cell transplant recipients.

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PTN treatment improves the survival of irradiated mice and hematopoietic...
(A) Survival of 700 cGy–irradiated mice treated intraperitoneally with 2 or 4 μg PTN or saline administered at +24 hours and every other day through day +14 (PTN-treated groups: 12 of 15 for both; saline-treated group: 5 of 15 mice; P = 0.002 for PTN 4 μg vs. saline, P = 0.004 for PTN 2 μg vs. saline). (B) Flow cytometric analysis of BM KSL cells from irradiated mice at day +10 treated with saline or PTN. (C) BM KSL cells and CFCs per femur (n = 6, *P = 0.02, **P = 0.0003). (D) Survival of irradiated mice treated subcutaneously, beginning at +48 hours and +96 hours, with PTN or saline (PTN 48 hours: 15 of 15 mice and PTN 96 hours: 13 of 15 mice; saline: 10 of 19 mice; P = 0.002 for PTN 48 hours vs. saline, P = 0.04 for PTN 96 hours vs. saline.). (E) Survival of irradiated mice transplanted with BM cells and treated with PTN or saline (PTN, 19 of 38 mice, 50% vs. saline, 6 of 36 mice, 17%; P = 0.003). (F) CFCs per femur at day +14 following transplantation and treatment with PTN or saline (n = 6, *P = 0.005). (G) H&E images (original magnification, ×63) of femurs at day +14 from transplanted mice treated with PTN or saline.