Genetic control of quiescence in hematopoietic stem cells

Figures & data

Figure 1. Models of bone marrow hematopoiesis. The current model of blood formation is a continuous process of the differentiation and progressive loss of stem cell features (quiescence, self-renewal, and multipotency).

Figure 2. Control of HSC quiescence. (A) HSC quiescence is controlled by stem cell extrinsic (SCE) and intrinsic (SCI) factors. Proliferating HSCs face multiple fates: differentiation, mobilization, death, senescence, and re-entry to quiescence. (B) Regulation of the exit from quiescence and entry into cell division by cell cycle regulators (activating in green and inhibitory in red).

Table 1. Stem cell-extrinsic (SCE) regulation of HSC quiescence

Ligand	Receptor	Mouse model	Effect on quiescence	References
Ang-1	Tie2	Immunophenotypic identification and functional characterization of Tie2-positive HSCs	Positive	61
THPO	Mpl	Immunophenotypic identification of Mpl-positive HSCs. Blocking signaling with anti-Mpl antibodies	Positive	62
Wnt	Frizzled	Transgenic mice expressing the Wnt inhibitor Dkk1 driven by an osteoblast-specific promoter	Positive	63
		Cross of mice with the insertion of the Myc-tagged stable form of human β-catenin into the R26 locus with Mx1-Cre mice	Negative	64
TGFβ	TGFBR	cKO TGFBRI (Mx1-Cre)	No effect at steady-state	65
		TGFβ levels during myelosuppression and blockade of TGFβ during recovery	Reset quiescence after cytoablation	11
IFNγ	IFNGR	IFNγ −/−, Mycobacterium avium infection	Negative	9
SDF1(CXCL12)	CXCR4	Cxcr4 −/−	Positive	66
OPN		Opn −/−	Positive	67 and 68
Hh	Patched	Gli1 −/− (downstream transcription factor) Ptc +/−	Negative	69 and 12
SCF	c-kit	SCF isoform −/− as a recipient	Positive	70

Table 2. Stem cell intrinsic (SCI) regulation of HSC quiescence

Category	Gene	Control of quiescence	Mouse model	References
Cell cycle	p21	Positive	−/−	13
	p27		−/−	16
	p18		−/−	14
	p57		cKO (Mx1-cre)	15 and 16
	Rb/p107/p130		cKO (Mx1-cre, Rosa26-cre ERt2)	71
	CyclinD1/D2/D3	Negative	−/−	72
	Cdk4/6		−/−	73
Transcription factor	JunB	Positive	cKO (MORE-cre)	18
	Pbx1		−/−, cKO (Mx1-cre, Tie2-cre)	19
	FoxO1/3/4		cKO (Mx1-cre)	20
	FoxO3a		−/−	21
	Nurr1		Retroviral-transduction	22
	Scl		+/−	74
	p53		−/−	24 and 75
	Necdin		−/−	76
	Egr1		−/−	28
	ELF4	Negative	−/−	23
	AML1/Runx1		cKO (Mx1-cre)	27
	Stat5		cKO (Mx1-cre)	29
Other	Fbw7	Positive	cKO (Mx1-cre), Retroviral expression	30 and 77
	Lkb1		cKO (Mx1-cre, Rosa26-cre ERt2)	9, 33, and 34
	Tsc1-mTOR		cKO (Mx1-cre)	36
	Cited2		cKO (Mx1-cre)	38 and 39
	Txnip		−/−	40
	Atm		−/−	78
	Mi-2β		cKO (Mx1-cre)	79
	Paf		−/−	80
	Ott1		cKO (Mx1-cre)	81
	G0S2		Retroviral expression and silencing	41
	Akt1/2	Negative	−/−	35
	Lnk		−/−	82 and 83

Figure 3. G0S2 promotes quiescence by interacting with nucleolin. (A) The arginine-glycine-glycine (RGG) domain of nucleolin interacts with a highly conserved hydrophobic domain (HD) of G0S2. (B) The ectopic expression of G0S2 retains nucleolin in the cytosol of quiescent HSCs (Lin⁻ Sca-1⁺ c-kit⁺ CD48⁻ CD150⁺ cells). (C) Diagram depicting a novel model that controls the quiescence of HSCs mediated by the interaction between G0S2 and nucleolin.

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004; 118:149 - 61; http://dx.doi.org/10.1016/j.cell.2004.07.004; PMID: 15260986

 PubMed Web of Science ®Google Scholar

Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 2007; 1:685 - 97; http://dx.doi.org/10.1016/j.stem.2007.10.020; PMID: 18371409

 PubMed Web of Science ®Google Scholar

Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2008; 2:274 - 83; http://dx.doi.org/10.1016/j.stem.2008.01.003; PMID: 18371452

 PubMed Web of Science ®Google Scholar

Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 2006; 7:1048 - 56; http://dx.doi.org/10.1038/ni1381; PMID: 16951689

 PubMed Web of Science ®Google Scholar

Larsson J, Blank U, Helgadottir H, Björnsson JM, Ehinger M, Goumans MJ, et al. TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood 2003; 102:3129 - 35; http://dx.doi.org/10.1182/blood-2003-04-1300; PMID: 12842983

 PubMed Web of Science ®Google Scholar

Brenet F, Kermani P, Spektor R, Rafii S, Scandura JM. TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med 2013; 210:623 - 39; http://dx.doi.org/10.1084/jem.20121610; PMID: 23440043

 PubMed Web of Science ®Google Scholar

Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 2010; 465:793 - 7; http://dx.doi.org/10.1038/nature09135; PMID: 20535209

 PubMed Web of Science ®Google Scholar

Nie Y, Han YC, Zou YR. CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med 2008; 205:777 - 83; http://dx.doi.org/10.1084/jem.20072513; PMID: 18378795

 PubMed Web of Science ®Google Scholar

Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grünewald E, et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med 2005; 201:1781 - 91; http://dx.doi.org/10.1084/jem.20041992; PMID: 15928197

 PubMed Web of Science ®Google Scholar

Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT, et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 2005; 106:1232 - 9; http://dx.doi.org/10.1182/blood-2004-11-4422; PMID: 15845900

 PubMed Web of Science ®Google Scholar

Merchant A, Joseph G, Wang Q, Brennan S, Matsui W. Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood 2010; 115:2391 - 6; http://dx.doi.org/10.1182/blood-2009-09-241703; PMID: 20107231

 PubMed Web of Science ®Google Scholar

Trowbridge JJ, Scott MP, Bhatia M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci U S A 2006; 103:14134 - 9; http://dx.doi.org/10.1073/pnas.0604568103; PMID: 16968775

 PubMed Web of Science ®Google Scholar

Driessen RL, Johnston HM, Nilsson SK. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region. Exp Hematol 2003; 31:1284 - 91; http://dx.doi.org/10.1016/j.exphem.2003.08.015; PMID: 14662336

 PubMed Web of Science ®Google Scholar

Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000; 287:1804 - 8; http://dx.doi.org/10.1126/science.287.5459.1804; PMID: 10710306

 PubMed Web of Science ®Google Scholar

Zou P, Yoshihara H, Hosokawa K, Tai I, Shinmyozu K, Tsukahara F, et al. p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 2011; 9:247 - 61; http://dx.doi.org/10.1016/j.stem.2011.07.003; PMID: 21885020

 PubMed Web of Science ®Google Scholar

Yuan Y, Shen H, Franklin DS, Scadden DT, Cheng T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol 2004; 6:436 - 42; http://dx.doi.org/10.1038/ncb1126; PMID: 15122268

 PubMed Web of Science ®Google Scholar

Matsumoto A, Takeishi S, Kanie T, Susaki E, Onoyama I, Tateishi Y, et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell 2011; 9:262 - 71; http://dx.doi.org/10.1016/j.stem.2011.06.014; PMID: 21885021

 PubMed Web of Science ®Google Scholar

Viatour P, Somervaille TC, Venkatasubrahmanyam S, Kogan S, McLaughlin ME, Weissman IL, et al. Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell 2008; 3:416 - 28; http://dx.doi.org/10.1016/j.stem.2008.07.009; PMID: 18940733

 PubMed Web of Science ®Google Scholar

Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E, et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 2004; 118:477 - 91; http://dx.doi.org/10.1016/j.cell.2004.07.025; PMID: 15315760

 PubMed Web of Science ®Google Scholar

Malumbres M, Sotillo R, Santamaría D, Galán J, Cerezo A, Ortega S, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 2004; 118:493 - 504; http://dx.doi.org/10.1016/j.cell.2004.08.002; PMID: 15315761

 PubMed Web of Science ®Google Scholar

Santaguida M, Schepers K, King B, Sabnis AJ, Forsberg EC, Attema JL, et al. JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal. Cancer Cell 2009; 15:341 - 52; http://dx.doi.org/10.1016/j.ccr.2009.02.016; PMID: 19345332

 PubMed Web of Science ®Google Scholar

Ficara F, Murphy MJ, Lin M, Cleary ML. Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell 2008; 2:484 - 96; http://dx.doi.org/10.1016/j.stem.2008.03.004; PMID: 18462698

 PubMed Web of Science ®Google Scholar

Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128:325 - 39; http://dx.doi.org/10.1016/j.cell.2007.01.003; PMID: 17254970

 PubMed Web of Science ®Google Scholar

Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1:101 - 12; http://dx.doi.org/10.1016/j.stem.2007.02.001; PMID: 18371339

 PubMed Web of Science ®Google Scholar

Sirin O, Lukov GL, Mao R, Conneely OM, Goodell MA. The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol 2010; 12:1213 - 9; http://dx.doi.org/10.1038/ncb2125; PMID: 21076412

 PubMed Web of Science ®Google Scholar

Lacombe J, Herblot S, Rojas-Sutterlin S, Haman A, Barakat S, Iscove NN, et al. Scl regulates the quiescence and the long-term competence of hematopoietic stem cells. Blood 2010; 115:792 - 803; http://dx.doi.org/10.1182/blood-2009-01-201384; PMID: 19850742

 PubMed Web of Science ®Google Scholar

Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, Huang G, et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 2009; 4:37 - 48; http://dx.doi.org/10.1016/j.stem.2008.11.006; PMID: 19128791

 PubMed Web of Science ®Google Scholar

Abbas HA, Pant V, Lozano G. The ups and downs of p53 regulation in hematopoietic stem cells. Cell Cycle 2011; 10:3257 - 62; http://dx.doi.org/10.4161/cc.10.19.17721; PMID: 21957490

 PubMed Web of Science ®Google Scholar

Asai T, Liu Y, Di Giandomenico S, Bae N, Ndiaye-Lobry D, Deblasio A, et al. Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells. Blood 2012; 120:1601 - 12; http://dx.doi.org/10.1182/blood-2011-11-393983; PMID: 22776820

 PubMed Web of Science ®Google Scholar

Min IM, Pietramaggiori G, Kim FS, Passegué E, Stevenson KE, Wagers AJ. The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2008; 2:380 - 91; http://dx.doi.org/10.1016/j.stem.2008.01.015; PMID: 18397757

 PubMed Web of Science ®Google Scholar

Lacorazza HD, Yamada T, Liu Y, Miyata Y, Sivina M, Nunes J, et al. The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 2006; 9:175 - 87; http://dx.doi.org/10.1016/j.ccr.2006.02.017; PMID: 16530702

 PubMed Web of Science ®Google Scholar

Ichikawa M, Goyama S, Asai T, Kawazu M, Nakagawa M, Takeshita M, et al. AML1/Runx1 negatively regulates quiescent hematopoietic stem cells in adult hematopoiesis. J Immunol 2008; 180:4402 - 8; PMID: 18354160

 PubMed Web of Science ®Google Scholar

Wang Z, Li G, Tse W, Bunting KD. Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood 2009; 113:4856 - 65; http://dx.doi.org/10.1182/blood-2008-09-181107; PMID: 19258595

 PubMed Web of Science ®Google Scholar

Reavie L, Della Gatta G, Crusio K, Aranda-Orgilles B, Buckley SM, Thompson B, et al. Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex. Nat Immunol 2010; 11:207 - 15; http://dx.doi.org/10.1038/ni.1839; PMID: 20081848

 PubMed Web of Science ®Google Scholar

Iriuchishima H, Takubo K, Matsuoka S, Onoyama I, Nakayama KI, Nojima Y, et al. Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression. Blood 2011; 117:2373 - 7; http://dx.doi.org/10.1182/blood-2010-07-294801; PMID: 21190997

 PubMed Web of Science ®Google Scholar

Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010; 468:653 - 8; http://dx.doi.org/10.1038/nature09571; PMID: 21124450

 PubMed Web of Science ®Google Scholar

Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 2010; 468:659 - 63; http://dx.doi.org/10.1038/nature09572; PMID: 21124451

 PubMed Web of Science ®Google Scholar

Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008; 205:2397 - 408; http://dx.doi.org/10.1084/jem.20081297; PMID: 18809716

 PubMed Web of Science ®Google Scholar

Kranc KR, Schepers H, Rodrigues NP, Bamforth S, Villadsen E, Ferry H, et al. Cited2 is an essential regulator of adult hematopoietic stem cells. Cell Stem Cell 2009; 5:659 - 65; http://dx.doi.org/10.1016/j.stem.2009.11.001; PMID: 19951693

 PubMed Web of Science ®Google Scholar

Du J, Chen Y, Li Q, Han X, Cheng C, Wang Z, et al. HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood 2012; 119:2789 - 98; http://dx.doi.org/10.1182/blood-2011-10-387902; PMID: 22308296

 PubMed Web of Science ®Google Scholar

Jeong M, Piao ZH, Kim MS, Lee SH, Yun S, Sun HN, et al. Thioredoxin-interacting protein regulates hematopoietic stem cell quiescence and mobilization under stress conditions. J Immunol 2009; 183:2495 - 505; http://dx.doi.org/10.4049/jimmunol.0804221; PMID: 19625652

 PubMed Web of Science ®Google Scholar

Maryanovich M, Oberkovitz G, Niv H, Vorobiyov L, Zaltsman Y, Brenner O, et al. The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 2012; 14:535 - 41; http://dx.doi.org/10.1038/ncb2468; PMID: 22446738

 PubMed Web of Science ®Google Scholar

Yoshida T, Hazan I, Zhang J, Ng SY, Naito T, Snippert HJ, et al. The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev 2008; 22:1174 - 89; http://dx.doi.org/10.1101/gad.1642808; PMID: 18451107

 PubMed Web of Science ®Google Scholar

Amrani YM, Gill J, Matevossian A, Alonzo ES, Yang C, Shieh JH, et al. The Paf oncogene is essential for hematopoietic stem cell function and development. J Exp Med 2011; 208:1757 - 65; http://dx.doi.org/10.1084/jem.20102170; PMID: 21844206

 PubMed Web of Science ®Google Scholar

Xiao N, Jani K, Morgan K, Okabe R, Cullen DE, Jesneck JL, et al. Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. Blood 2012; 119:4898 - 907; http://dx.doi.org/10.1182/blood-2012-01-403089; PMID: 22490678

 PubMed Web of Science ®Google Scholar

Yamada T, Park CS, Burns A, Nakada D, Lacorazza HD. The cytosolic protein G0S2 maintains quiescence in hematopoietic stem cells. PLoS One 2012; 7:e38280; http://dx.doi.org/10.1371/journal.pone.0038280; PMID: 22693613

 PubMed Web of Science ®Google Scholar

Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 2010; 115:4030 - 8; http://dx.doi.org/10.1182/blood-2009-09-241000; PMID: 20354168

 PubMed Web of Science ®Google Scholar

Bersenev A, Wu C, Balcerek J, Tong W. Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J Clin Invest 2008; 118:2832 - 44; PMID: 18618018

 PubMed Web of Science ®Google Scholar

Suzuki N, Yamazaki S, Ema H, Yamaguchi T, Nakauchi H, Takaki S. Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL. Exp Hematol 2012; 40:166 - 74, e3; http://dx.doi.org/10.1016/j.exphem.2011.11.003; PMID: 22101255

 PubMed Web of Science ®Google Scholar