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.
View: Text | PDF
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

×

Figure 2

RAS signaling is necessary for PTN-mediated HSPC expansion.

Options: View larger image (or click on image) Download as PowerPoint
RAS signaling is necessary for PTN-mediated HSPC expansion. (A) p-ALK ex...
(A) p-ALK expression in BM KSL cells from the represented groups (n = 3, *P = 0.003). (B) p-GRB2 expression in BM KSL cells treated with media alone (gray curve) or PTN (red curve), with mean percentage p-GRB2 levels shown (n = 3, *P < 0.0001). (C) Representative p-ERK1/2 expression in KSL cells treated with media alone (gray curve) or PTN (red curve), with mean percentage p-ERK1/2 levels shown (n = 5, *P < 0.001). (D) p-ERF expression (green) in BM KSL cells cultured with thrombopoietin, SCF, and FLT-3 ligand (TSF), with or without PTN, and scatter plot of p-ERF levels in KSL cells (horizontal bars represent means; n = 12, *P < 0.0001). Scale bar: 10 μm. (E) CFCs per input KSL cells and percentage CFU-GEMMs at day +7 of the represented cultures (n = 3, *P = 0.04, **P = 0.01, #P = 0.02, ##P = 0.03). (F) CD45.1+ donor cell engraftment at 8 weeks following competitive transplantation of the progeny of 10 CD34–KSL cells cultured in the conditions shown (n = 7–11 per group, *P = 0.04, **P < 0.0001).