Neutral Sphingomyelinase Blockade Enhances Hematopoietic Stem Cell Fitness Through an Integrated Stress Response

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2023 Sep 12

PMID 37699202

Authors

Stephanie N Hurwitz

Seul K Jung

Danielle R Kobulsky

Hossein Fazelinia

Lynn A Spruce

Empar Baltasar Perez

Nathalie Groen

Clementina Mesaros

Peter Kurre

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC-graft products are limited by barriers in maintaining critical self-renewal and quiescence properties. The role of sphingolipid metabolism in safeguarding these essential cellular properties has been recently recognized, but not yet widely explored. Here, we demonstrate that pharmacologic and genetic inhibition of neutral sphingomyelinase 2 (nSMase-2) leads to sustained improvements in long-term competitive transplantation efficiency after ex vivo culture. Mechanistically, nSMase-2 blockade activates a canonical integrated stress response (ISR) and promotes metabolic quiescence in human and murine HSPCs. These adaptations result in part from disruption in sphingolipid metabolism that impairs the release of nSMase-2-dependent extracellular vesicles (EVs). The aggregate findings link EV trafficking and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, transient nSMase-2 inhibition enables ex vivo graft manipulation with enhanced HSPC potency.

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