Id1 Ablation Protects Hematopoietic Stem Cells from Stress-Induced Exhaustion and Aging

Publication date: Available online 28 June 2018

Source: Cell Stem Cell

Author(s): Satyendra K. Singh, Shweta Singh, Stephen Gadomski, Lei Sun, Alexander Pfannenstein, Valentin Magidson, Xiongfong Chen, Serguei Kozlov, Lino Tessarollo, Kimberly D. Klarmann, Jonathan R. Keller

Summary

Defining mechanisms that maintain tissue stem cells during homeostasis, stress, and aging is important for improving tissue regeneration and repair and enhancing cancer therapies. Here, we show that Id1 is induced in hematopoietic stem cells (HSCs) by cytokines that promote HSC proliferation and differentiation, suggesting that it functions in stress hematopoiesis. Genetic ablation of Id1 increases HSC self-renewal in serial bone marrow transplantation (BMT) assays, correlating with decreases in HSC proliferation, mitochondrial biogenesis, and reactive oxygen species (ROS) production. Id1^−/− HSCs have a quiescent molecular signature and harbor less DNA damage than control HSCs. Cytokines produced in the hematopoietic microenvironment after γ-irradiation induce Id1 expression. Id1^−/− HSCs display a blunted proliferative response to such cytokines and other inducers of chronic proliferation including genotoxic and inflammatory stress and aging, protecting them from chronic stress and exhaustion. Thus, targeting Id1 may be therapeutically useful for improving HSC survival and function during BMT, chronic stress, and aging.

Graphical Abstract

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