EPFL BioE Talks SERIES "Metabolic and Stress Response Regulation in Human Hematopoietic and Leukemia Stem Cells"


Event details

Date 29.11.2021 16:0017:00  
Speaker Stephanie Xie, Ph.D., Princess Margaret Cancer Centre, University Health Network, University of Toronto (Can)
Location Online
Category Conferences - Seminars
Event Language English

The hundreds of billions of blood cells produced in the body daily are ultimately derived from a rare subpopulation called long-term hematopoietic stem cells (LT-HSC). LT-HSC play a central role in maintaining life-long hematopoiesis and are characterized by three functional hallmarks: self-renewal, multilineage differentiation, and capacity to remain quiescent for long periods of time. Improving our understanding of LT-HSC has implications for a number of diseases including immune system disorders, inherited blood disorders, and various cancers. Indeed, some leukemias, e.g. acute myeloid leukemia (AML), are considered stem cell diseases that are caricatures of the normal blood system. Inflammatory stress is a major risk factor for many diseases including AML. Severe infections such as COVID-19 or bacterial sepsis lead to excessive production of pro-inflammatory cytokines (e.g. TNFα) which has been shown to drive lymphopenia, organ failure, and mortality in some individuals. Upon stress stimuli such as infection, HSCs must exit quiescence and respond to sudden changes in demand. However, the molecular programs underlying inflammatory stress response in human LT-HSC are not well understood. There is a critical unmet need to characterize inflammatory stress regulation in human LT-HSC and use this knowledge to develop inflammatory stress interventions in disease that spare LT-HSC.
Metabolism, derived from the Greek term metaballein (to change), is intimately tied to the ability for HSCs to transition from quiescence to a proliferative state. We recently identified that programs involving sphingolipid metabolism and stress response, including inflammatory stress, regulate human LT-HSC function and show these are dysregulated in AML. I will discuss how sphingolipid composition is diverse across the human hematopoietic hierarchy and sphingolipid metabolism regulates LT-HSC self-renewal. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that contributes to a number of inflammatory conditions including neurodegeneration, autoimmunity, and cardiovascular disease. In a second story, I will describe how S1PR3 was identified as a TNFa activated S1P receptor whose lentiviral overexpression in LT-HSC was sufficient to promote cell cycle activation, drive myeloid differentiation and led to decreased reconstitution in xenografts akin to a chronic inflammation-induced emergency myelopoiesis response. Functional studies involving modulation of the S1P signaling axis, including with the S1P prodrug FTY720, in LSCs induced differentiation and reduced engraftment ability, pointing to a novel therapeutic approach in AML. Finally, I will discuss a new project seeking to characterize the effect of pro-inflammatory stress on human LT-HSC and identify potential novel metabolic pathways that prevent HSC functional impairment due to pro-inflammatory stress exposures. Preliminary data suggest TNFα elicits heterogeneous responses from the human LT-HSC pool with some cells primed to respond and others more resistant to the negative impact of TNFα treatment.

Stephanie Xie is an affiliate scientist (equivalent to a research assistant professor) at the Princess Margaret Cancer Centre in the University Health Network. She obtained her PhD from the Department of Biology at the Massachusetts Institute of Technology with Dr. Peter Sorger, moved to a post-doctoral fellowship in Dr. David Scadden’s group at Massachusetts General Hospital/Harvard Stem Cell Institute and then finished her post-doctoral training in Dr. John Dick’s group at the Princess Margaret Cancer Centre. She is one of the leading experts of human HSC assays/analysis. She has been at the forefront in the functional characterization of stemness programs in human hematopoietic stem cells (HSCs) and how they are perturbed in leukemia stem cells (LSCs) from acute myeloid leukemia (AML). She identified that sphingolipids intersect with stemness regulatory programs including inflammatory and proteostatic quality control pathways to regulate cell fate in human HSCs and this has been subverted in patient LSCs. Understanding lipid metabolism in stem cells holds great translational promise including improving HSC transplantation and targeting AML. 

Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks

This seminar can be followed via Zoom web-streaming only, (following prior one-time registration through the link above).

Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
Please make sure to
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