Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
International Journal of Hematology
Published in: International Journal of Hematology 6/2018

01-06-2018 | Progress in Hematology

Regulation of unfolded protein response in hematopoietic stem cells

Authors: Valgardur Sigurdsson, Kenichi Miharada

Published in: International Journal of Hematology | Issue 6/2018

Login to get access

Abstract

Hematopoietic stem cells (HSCs) play a central role in hematopoietic regeneration, which has been demonstrated by thorough studies. In contrast, the cell cycle status and metabolic condition of HSCs define these cells as dormant. Recent studies have also revealed that protein metabolism is quite unique, as dormant HSCs have a lower protein synthesis rate and folding capacity. Under proliferative conditions, upon hematopoietic stress, HSCs need to deal with higher requirements of protein production to achieve fast and effective blood replenishment. In such cases, increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and misfolded proteins. In turn, this triggers endoplasmic reticulum (ER) stress as a part of the unfolded protein response (UPR). Since ER stress is a multi-layered, bidirectional cellular response that contains both positive (survival) and negative (death) reactions, proper management of UPR and ER stress signals is crucial for HSCs and also for maintaining the healthy hematopoietic system. In this review, we introduce the latest findings in this emerging field within hematopoiesis and HSC regulation.
Literature
1.
2.
3.
4.
5.
6.
Sigurdsson V, Takei H, Soboleva S, et al. Bile acids protect expanding hematopoietic stem cells from unfolded protein stress in fetal liver. Cell Stem Cell. 2016;18(4):522–32.CrossRefPubMed
7.
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.CrossRefPubMed
8.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29.CrossRefPubMed
9.
Miharada K, Sigurdsson V, Karlsson S. Dppa5 improves hematopoietic stem cell activity by reducing endoplasmic reticulum stress. Cell Rep. 2014;7(5):1381–92.CrossRefPubMed
10.
van Galen P, Kreso A, Mbong N, et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature. 2014;510(7504):268–72.CrossRefPubMed
11.
12.
Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002;295(5561):1852–8.CrossRefPubMed
13.
14.
Tannous A, Pisoni GB, Hebert DN, et al. N-linked sugar-regulated protein folding and quality control in the ER. Semin Cell Dev Biol. 2015;41:79–89.CrossRefPubMed
15.
Kim YE, Hipp MS, Bracher A, et al. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013;82:323–55.CrossRefPubMed
16.
Morrow G, Hightower LE, Tanguay RM. Small heat shock proteins: big folding machines. Cell Stress Chaperones. 2015;20(2):207–12.CrossRefPubMed
17.
Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol. 2005;7(8):766–72.CrossRefPubMed
18.
Bozaykut P, Ozer NK, Karademir B. Regulation of protein turnover by heat shock proteins. Free Radic Biol Med. 2014;77:195–209.CrossRefPubMed
19.
Luo B, Lee AS. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 2013;32(7):805–18.CrossRefPubMed
20.
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.CrossRefPubMed
21.
22.
Yoshida H. Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal. 2007;9(12):2323–33.CrossRefPubMed
23.
Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881 – 91.CrossRefPubMed
24.
Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem. 2003;278(37):34864–73.CrossRefPubMed
25.
Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12(7):982 – 95.CrossRefPubMedPubMedCentral
26.
Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833(12):3460–70.CrossRefPubMed
27.
Eizirik DL, Cnop M. ER stress in pancreatic beta cells: the thin red line between adaptation and failure. Sci Signal. 2010;3(110):pe7.CrossRefPubMed
28.
Gass JN, Gunn KE, Sriburi R, et al. Stressed-out B cells? Plasma-cell differentiation and the unfolded protein response. Trends Immunol. 2004;25(1):17–24.CrossRefPubMed
29.
Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412(6844):300–7.CrossRefPubMed
30.
31.
Halbleib K, Pesek K, Covino R, et al. Activation of the unfolded protein response by lipid bilayer stress. Mol Cell. 2017;67(4):673–84.e8.CrossRefPubMed
32.
Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298–310.CrossRefPubMed
33.
Miharada K, Karlsson G, Rehn M, et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell. 2011;9(4):330–44.CrossRefPubMed
34.
Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8(11):851–64.CrossRefPubMed
35.
Rouault-Pierre K, Lopez-Onieva L, Foster K, et al. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell. 2013;13(5):549–63.CrossRefPubMed
36.
Iwawaki T, Akai R, Kohno K, et al. A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med. 2004;10(1):98–102.CrossRefPubMed
37.
Zhao Y, Zhou J, Liu D, et al. ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver. Blood. 2015;126(21):2383–91.CrossRefPubMedPubMedCentral
38.
Iwawaki T, Akai R, Yamanaka S, et al. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci USA. 2009;106(39):16657–62.CrossRefPubMedPubMedCentral
39.
Reimold AM, Etkin A, Clauss I, et al. An essential role in liver development for transcription factor XBP-1. Genes Dev. 2000;14(2):152–7.PubMedPubMedCentral
40.
Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell. 2007;13(3):365–76.CrossRefPubMed
41.
Pina C, Teles J, Fugazza C, et al. Single-cell network analysis identifies Ddit3 as a nodal lineage regulator in hematopoiesis. Cell Rep. 2015;11(10):1503–10.CrossRefPubMedPubMedCentral
42.
Walasek MA, van Os R, de Haan G. Hematopoietic stem cell expansion: challenges and opportunities. Ann N Y Acad Sci. 2012;1266:138–50.CrossRefPubMed
43.
Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51.CrossRefPubMed
44.
Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40.CrossRefPubMedPubMedCentral
45.
Ema H, Nakauchi H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood. 2000;95(7):2284–8.PubMed
46.
Mikkola H, Orkin SH. The journey of developing hematopoietic stem cells. Development. 2006;133(19):3733–44.CrossRefPubMed
47.
Nakagawa M, Setchell KD. Bile acid metabolism in early life: studies of amniotic fluid. J Lipid Res. 1990;31(6):1089–98.PubMed
48.
Itoh S, Onishi S. Hepatic taurine, glycine and individual bile acids in early human fetus. Early Hum Dev. 2000;57(1):71–7.CrossRefPubMed
49.
50.
Rosen H, Reshef A, Maeda N, et al. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted Sterol 27-hydroxylase gene. J Biol Chem. 1998;273(24):14805–12.CrossRefPubMed
51.
Boyce M, Bryant KF, Jousse C, et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005;307(5711):935–9.CrossRefPubMed
52.
Bershtein S, Mu W, Serohijos AW, et al. Protein quality control acts on folding intermediates to shape the effects of mutations on organismal fitness. Mol Cell. 2013;49(1):133–44.CrossRefPubMed
53.
Li-Hawkins J, Gåfvels M, Olin M, et al. Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest. 2002;110(8):1191–200.CrossRefPubMedPubMedCentral
54.
Nakada D, Oguro H, Levi BP, et al. Oestrogen increases haematopoietic stem- cell self-renewal in females and during pregnancy. Nature. 2014;505(7484):555–8.CrossRefPubMedPubMedCentral
55.
Chapple RH, Hu T, Tseng YJ, et al. ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response. Elife. 2018;7:e31159.CrossRefPubMedPubMedCentral
56.
Wahlestedt M, Pronk CJ, Bryder D. Concise review: hematopoietic stem cell aging and the prospects for rejuvenation. Stem Cells Transl Med. 2015;4(2):186–94.CrossRefPubMed
57.
58.
Luchsinger LL, de Almeida MJ, Corrigan DJ, et al. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529(7587):528–31.CrossRefPubMedPubMedCentral
59.
Qian P, He XC, Paulson A, et al. The Dlk1-Gtl2 locus preserves lt-hsc function by inhibiting the PI3K-mTOR pathway to restrict mitochondrial metabolism. Cell Stem Cell. 2016;18(2):214–28.CrossRefPubMed
60.
Ito K, Turcotte R, Cui J, et al. Self-renewal of a purified Tie2 + hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016;354(6316):1156–60.CrossRefPubMedPubMedCentral
61.
Ansó E, Weinberg SE, Diebold LP, et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol. 2017;19(6):614–25.CrossRefPubMedPubMedCentral
62.
63.
Mohrin M, Shin J, Liu Y, et al. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science. 2015;347(6228):1374–7.CrossRefPubMedPubMedCentral
64.
Metadata
Title
Regulation of unfolded protein response in hematopoietic stem cells
Authors
Valgardur Sigurdsson
Kenichi Miharada
Publication date
01-06-2018
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 6/2018
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-018-2458-7

Other articles of this Issue 6/2018

International Journal of Hematology 6/2018 Go to the issue

Original Article

Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan

Original Article

Favorable survival in lung transplant recipients on preoperative low-dose, as compared to high-dose corticosteroids, after hematopoietic stem cell transplantation

Progress in Hematology

The hematopoietic stem cell diet

Progress in Hematology

The significance and application of vascular niche in the development and maintenance of hematopoietic stem cells

Original Article

Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan

Original Article

Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits