Getting more for your marrow: boosting hematopoietic stem cell numbers with PGE2

Abstract

Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) self-renew and differentiate into lineages that include erythrocytes, platelets and all immune cells. HSC transplantation offers a potentially curative treatment for a number of hematopoietic and non-hematopoietic malignancies as well as immune and genetic disorders. Limited availability of immune-matched donors reduces the viable options for many patients in need of HSC transplantation, particularly those of diverse racial and ethnic backgrounds. Due to rapid availability and less stringent immune-matching requirements, umbilical cord blood (UCB) has emerged as a valuable source of transplantable HSCs. A single UCB unit contains a suboptimal number of HSCs for treating larger children or adults and there has thus been great clinical interest in expanding UCB HSCs ex vivo for use in transplantation. In this review we discuss the latest research and future avenues for the therapeutic use of small lipid mediator dmPGE2 to expand HSC numbers for transplantation. Originally identified in a chemical screen in zebrafish, dmPGE2 has now advanced to a phase II clinical trial as a therapy for patients with leukemia and lymphoma who are undergoing UCB transplantation.

Keywords: Engraftment; Ex Vivo expansion; Hematopoietic stem cells; Prostaglandin E(2); Self-renewal; Umbilical cord blood transplantation.

Figure 1. dmPGE₂ regulates vertebrate HSC function

(A) A schematic representation depicts the basic workflow for the zebrafish chemical screen that identified dmPGE₂ and an endogenous role for prostaglandin signaling in HSC formation. Adult zebrafish were in-crossed and collected embryos were treated with chemicals from the 3-somite stage to 36 hours post fertilization. Whole embryo in situ hybridization to runx1/cmyb (conserved HSC markers) was then used to examine HSC formation. Embryos treated with the stable derivative dmPGE₂ displayed increased runx1/cmyb staining in the AGM whereas treatment with the Cox inhibitor indomethacin led to reduced HSC formation. (B) 2-hour ex vivo pulse treatment with dmPGE₂ leads to increases in HSC function that last for as long as five serial transplantations. (C) Prolonged in vivo exposure to dmPGE₂ leads to enhanced engraftment; however, the treated cells eventually exhaust and lose differentiation potential. (D) dmPGE₂ signals through EP2 and EP4 receptors and an interaction with Wnt signaling. Downstream transcriptional changes lead to improved homing, survival and proliferation of the HSCs.

Figure 2. The clinical application of dmPGE₂ to improve UCB transplantation

The schematic on the left depicts the standard protocol in which two UCB units are administered to the patient. The clinical strategy for using dmPGE₂ to improve UCB transplantation is shown on the right. The first UCB unit is treated with a 2-hour ex vivo pulse of dmPGE₂ before infusion into the patient. A second untreated UCB is administered in succession. Clinical outcomes for each group are listed at the bottom of the figure.