Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to exvivo culture stress and aging.

Miriama Kruta,Mary Jean Sunshine,Yunpeng Fu,Bernadette A. Chua,Lorena Hidalgo San Jose,Robert A.J. Signer,Christopher H. Dillingham,Bijou De Jong,Ashu Chawla,Fanny J. Zhou

doi:10.1016/j.stem.2021.07.009

Abstract

Maintaining proteostasis is key to resisting stress and promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions of proteostasis contribute to stem cell aging is largely unexplored. We determined that ex-vivo-cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance exvivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs invivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.

Highlights

Hematopoietic stem cells (HSCs) regenerate blood and immune cells throughout life
HSCs may be subject to significant protein stress (Chambers et al, 2007; Chua et al, 2020), and the ability to respond to these acute and chronic stressors is critical for maintaining protein homeostasis
We previously discovered that young adult HSCs have lower protein synthesis rates than other hematopoietic cells (Signer et al, 2014)

Summary

Introduction

Hematopoietic stem cells (HSCs) regenerate blood and immune cells throughout life. To maintain life-long stem cell function and tissue integrity, HSCs depend on specialized stress response mechanisms to mitigate replicative (Alvarez et al, 2015; Flach et al, 2014; Xiao et al, 2012), metabolic (Gan et al, 2010; Gurumurthy et al, 2010; Karigane et al, 2016; Mohrin et al, 2015; Nakada et al, 2010; Takubo et al, 2013; Yu et al, 2013), oxidative (Abbas et al, 2010; Ito et al, 2004, 2006; Maryanovich et al, 2015; Tothova et al, 2007), and genotoxic stress (Beerman et al, 2014; Milyavsky et al, 2010; Mohrin et al, 2010; Rossi et al, 2007; Walter et al, 2015; Wang et al, 2012). Little is known about the factors that regulate proteostasis during stress in stem cells (Chua and Signer, 2020). The master regulator of this pathway is heat shock factor 1 (Hsf1), which encodes a highly conserved transcription factor that promotes proteostasis maintenance (Anckar and Sistonen, 2011). Under conditions of protein stress, the chaperones dissociate from Hsf to bind unfolded/misfolded proteins. This enables Hsf to translocate to the nucleus, where it classically induces transcription of heat shock proteins—molecular chaperones that coordinate protein folding, trafficking, and degradation to enhance proteostasis and promote cell survival (Anckar and Sistonen, 2011; Mendillo et al, 2012)

Methods

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Discussion

Conclusion