Eupalinilide E Inhibits Erythropoiesis and Promotes the Expansion of Hematopoietic Progenitor Cells

Abstract

Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to all blood cells. The ability to control HSC differentiation has the potential to improve the success of bone marrow transplants and the production of functional blood cells ex vivo. Here we performed an unbiased screen using primary human CD34(+) hematopoietic stem and progenitor cells (HSPCs) to identify natural products that selectively control their differentiation. We identified a plant-derived natural product, eupalinilide E, that promotes the ex vivo expansion of HSPCs and hinders the in vitro development of erythrocytes. This activity was additive with aryl hydrocarbon receptor (AhR) antagonists, which are also known to expand HSCs and currently in clinical development. These findings reveal a new activity for eupalinilide E, and suggest that it may be a useful tool to probe the mechanisms of hematopoiesis and improve the ex vivo production of progenitors for therapeutic purposes.

The Effects of Sesquiterpene Lactones on the Differentiation of Human or Animal Cells Cultured In-Vitro: A Critical Systematic Review

“…A total of 13 different cell lines originated from humans, mice, and rats were evaluated in the studies ( Figure 3 ). Among them, four cells were cancer cell lines including, mice melanoma B16 cells ( Ye et al, 2011 ), human HL-60 cell line ( Choi et al, 2002 ; Kim et al, 2005 ; Kim et al, 2006 ; Kweon et al, 2015 ), human CML cell line K562 ( Huang et al, 2016 ; Cai et al, 2017 ), human AML cell line U937 ( Huang et al, 2016 ), three cells were stem cells including rat mesenchymal stem cell ( Li et al, 2012 ), mice mesenchymal stem cells C3H10T1/2 ( Kim et al, 2017 ), hematopoietic stem and progenitor cells (HSPCs) ( de Lichtervelde et al, 2013 ), and six cells were normal cell lines including, 3T3-L1 cell line ( Galvis et al, 2011 ; Jang, 2016 ; Kim et al, 2016 ; Abood et al, 2018 ; Kwak and Kim, 2019 ), mice bone marrow macrophage ( Cheon et al, 2014 ; Hu et al, 2019 ; Lee et al, 2019 ; Li et al, 2019 ; Zhou et al, 2019 ; Lu et al, 2020 ), CD4 + T cell ( Park et al, 2016 ), human periosteum-derived cells ( Park et al, 2020 ), human preadipocytes ( Jang, 2016 ), mice MC3T3-E1 cell line ( Kim et al, 2017 ). All cell lines except the murine melanoma B16 cell line had a mesodermal origin.…”

Synthetic Route Development for the Laboratory Preparation of Eupalinilide E

“…The aqueous mixture was extracted with Et 2 O (3 × 100 mL), and the combined organic layers were washed with brine (1 × 50 mL), dried over Na 2 SO 4 , and concentrated in vacuo. The crude material was purified via silica gel column chromatography using 10/1 hexanes/ EtOAc to give the triene 24 (2.19 g, 6.22 mmol, 37%) as a yellow oil: R f = 0.5 (silica gel, 10/1 hexanes/EtOAc); 1 ((2S,3S)-2-((1R,4R,5R)-4-((4-Methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-4-methylenetetrahydrofuran-3-yl)methanol (26). To a stirred solution of triene 24 (1.36 g, 3.86 mmol, 1.0 equiv) in PhMe (38.6 mL, 0.1 M) at 23 °C were added solid bis(pinacolato)diboron (1.08 g, 4.24 mmol, 1.1 equiv), solid palladium(II) acetate (43 mg, 0.19 mmol, 0.05 equiv), and neat MeOH (0.16 mL, 72.1 mmol, 1.0 equiv).…”

“…From a relatively small library of natural products of variable origin (∼700 compounds), eupalinilide E was shown to markedly drive the expansion of HSPCs and inhibit differentiation, leading to a large increase in the number of HSPCs. 26 This effect was possible using either cord blood or human mobilized peripheral blood. Remarkably, this proliferative effect was demonstrated at 600 nM, approximately 20-fold of the concentration used previously to kill A549 lung cancer cells.…”

“…Natural products that modulate the tailoring of histones have been found to be capable of expanding HSPCs. − Schultz and co-workers screened Novartis’ natural product collection in an effort to discover new chemicals capable of promoting HSPC expansion. From a relatively small library of natural products of variable origin (∼700 compounds), eupalinilide E was shown to markedly drive the expansion of HSPCs and inhibit differentiation, leading to a large increase in the number of HSPCs . This effect was possible using either cord blood or human mobilized peripheral blood.…”

Modalities to Improve Cord Blood Engraftment

“…De Lichtervelde et al [24] have identified a new pharmacological agent, Eupalinilide E that inhibits erythropoiesis and promotes the expansion of hematopoietic progenitor cells. The activity of Eupalinilide E, a natural product, was found to have additive effects with AhR antagonists.…”