UM171 Induces a Homeostatic Inflammatory-detoxification Response Supporting Human HSC Self-renewal

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Nov 9

PMID 31703090

Citations 24

Authors

Jalila Chagraoui

Bernhard Lehnertz

Simon Girard

Jean Francois Spinella

Iman Fares

Elisa Tomellini

Nadine Mayotte

Sophie Corneau

Tara MacRae

Laura Simon

Guy Sauvageau

Affiliations

Soon will be listed here.

Abstract

Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.

Citing Articles

Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.

Coulombe P, Tomellini E, Chagraoui J, Mayotte N, Sauvageau G Nat Commun. 2025; 16(1):195.

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Advances in hematopoietic stem cells ex vivo expansion associated with bone marrow niche.

Deng J, Tan Y, Xu Z, Wang H Ann Hematol. 2024; 103(12):5035-5057.

PMID: 38684510 DOI: 10.1007/s00277-024-05773-1.

Effects of different concentrations of nicotinamide on hematopoietic stem cells cultured .

Ren Y, Cui Y, Wang H World J Stem Cells. 2024; 16(2):163-175.

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AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells.

Manesia J, Maganti H, Almoflehi S, Jahan S, Hasan T, Pasha R Cell Rep Methods. 2023; 3(12):100663.

PMID: 38070507 PMC: 10783628. DOI: 10.1016/j.crmeth.2023.100663.

An interactive resource of molecular signalling in the developing human haematopoietic stem cell niche.

Crosse E, Binagui-Casas A, Gordon-Keylock S, Rybtsov S, Tamagno S, Olofsson D Development. 2023; 150(23).

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