Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells

Annika Scheffold,Martin D Burkhalter,Friedrich Becker,Johann M Kraus,Marco Groth,Stephan Stilgenbauer,Melanie Philipp,Alush I Avila,Florian Schmid,Zhiyang Chen,Hans A Kestler,Yohei Morita,Sarah E Von Löhneysen,André Lechel,Ali H Baig

doi:10.1038/s41375-019-0641-3

Abstract

Accumulation of DNA damage and myeloid-skewed differentiation characterize aging of the hematopoietic system, yet underlying mechanisms remain incompletely understood. Here, we show that aging hematopoietic progenitor cells particularly of the myeloid branch exhibit enhanced resistance to bulky DNA lesions—a relevant type of DNA damage induced by toxins such as cancer drugs or endogenous aldehydes. We identified aging-associated activation of the Hedgehog (Hh) pathway to be connected to this phenotype. Inhibition of Hh signaling reverts DNA damage tolerance and DNA damage-resistant proliferation in aged hematopoietic progenitors. Vice versa, elevating Hh activity in young hematopoietic progenitors is sufficient to impair DNA damage responses. Altogether, these findings provide experimental evidence for aging-associated increases in Hh activity driving DNA damage tolerance in myeloid progenitors and myeloid-skewed differentiation. Modulation of Hh activity could thus be explored as a therapeutic strategy to prevent DNA damage tolerance, myeloid skewing, and disease development in the aging hematopoietic system.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Given the pivotal role of stem cells in tissue maintenance and cancer formation, the protection of stem cells from DNA damage appears to be of utmost importance for the evolution of long-lived vertebrate species
This is illustrated by an accumulation of markers for DNA damage in hematopoietic stem cells (HSCs) of normally aging, repair-proficient mice and men [5, 7], the nature of the origin for this accumulation is under debate and may involve defects in resolving the persistence of phosphorylated DNA damage response factors [8]
We report that aging triggers elevated Hh signaling activity in the hematopoietic system, in myeloid-biased HSCs and myeloid progenitors

Summary

Introduction

The hematopoietic system is sensitive to defects in molecular pathways governing DNA repair and genomic stability, which is reflected in premature exhaustion of hematopoietic stem cells (HSCs) upon failure of genome integrity maintenance systems [3,4,5,6]. This is illustrated by an accumulation of markers for DNA damage in HSCs of normally aging, repair-proficient mice and men [5, 7], the nature of the origin for this accumulation is under debate and may involve defects in resolving the persistence of phosphorylated DNA damage response factors [8]

Objectives

Methods

Results

Conclusion