Regulation of hematopoietic stem cells by their mature progeny

Graaf, Carolyn A. de; Kauppi, Maria; Baldwin, Tracey M.; Hyland, Craig D.; Metcalf, Donald; Willson, Tracy A.; Carpinelli, Marina R.; Smyth, Gordon K.; Alexander, Warren S.; Hilton, Douglas J.

doi:10.1073/pnas.1016166108

Cited by 65 publications

(75 citation statements)

References 45 publications

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“…We confirmed this finding using the alternative method of Ki67-antibody staining for proliferating cells and DAPI for DNA content. 29 Again, we observed significantly less G 0 and more G 1 cells in Wif1-LSKCD48 Ϫ populations ( Figure 4A right).…”

Section: Hscs In Wif1 Mice Are Less Quiescentmentioning

confidence: 81%

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Schaniel

Sirabella²,

Qiu³

et al. 2011

Blood

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The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions. (Blood. 2011; 118(9):2420-2429) IntroductionHematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate, producing blood cells throughout life. In the adult, the balance of self-renewal and differentiation is tightly regulated by cross-talk between HSCs and specialized cells within the bone marrow (BM) constituting the stem cell niche. This molecular dialogue is beginning to be explored, repeatedly implicating the Wnt signaling pathway. Wnt signaling can be mediated through either canonical ␤-catenin-mediated Lef/Tcf transcriptional activity or other noncanonical pathways. 1,2 Signaling is initiated in most all pathways through binding of Wnts to Frizzled (Fzd) receptors. There are multiple Wnts and Fzds allowing for many ligand/receptor combinations. On the other hand, Wnt signaling can be inhibited by several regulatory molecules. The Dickkopf family (Dkk) actively prevents binding of Wnt to Fzd and its coreceptors low-density lipoprotein receptor-related proteins 5 and 6, inhibiting canonical signaling, whereas secreted Fzd-related proteins (Sfrps) and Wnt inhibitory factor 1 (Wif1) bind Wnt proteins and sequester them in the extracellular space thus inhibiting both pathways. 3 Evidence for a role of Wnt proteins in hematopoiesis arose from experiments demonstrating that multiple Wnts could expand hematopoietic stem/progenitor cells (HSPCs) in culture. 4,5 Subsequently, culture of single HSCs, in the presence of purified Wnt3a, resulted in expansion concomitant with maintenance of phenotype and robust repopulating activity. 6 In addition, retroviral expression of constitutively active ␤-catenin in HSCs allowed their expansion in vitro without loss of rec...

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Section: Hscs In Wif1 Mice Are Less Quiescentmentioning

confidence: 81%

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Schaniel

Sirabella²,

Qiu³

et al. 2011

Blood

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“…This occurs most commonly through the release of cytokines that act on HSCs. For example, in mutant mice with defective megakaryopoiesis, Thpo levels are altered, resulting in impaired HSC function [106]. HSC regulation by mature blood cells can also occur indirectly via the niche as macrophages have been demonstrated to interact with Nestin 1 cells to prevent egress of…”

Section: Other Hematopoietic Cellsmentioning

confidence: 99%

Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development

2014

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The hematopoietic system has been intensely studied for many decades. For this reason, it has become the best understood stem cell-derived system that serves as a paradigm for stem cell biology and has found numerous applications in the clinics. While a lot of progress has recently been made in describing the bone marrow components that maintain and control blood stem cell function in the adult, very little is currently known about the regulatory microenvironment in which the first adult-repopulating hematopoietic stem cells are formed during development. Knowledge of these processes is crucial for understanding the basic regulation of hematopoietic stem cell production and behavior and to allow their in vitro expansion and generation from embryonic stem cells or iPS cells for clinical and research purposes. This review summarizes the recent advances that have been made in defining the cellular components, as well as the soluble and physical factors, that are part of the niche involved in regulating hematopoietic stem cell generation in the embryo. The findings are compared with what is known about the adult bone marrow niche to find common pathways for stem cell regulation, but also to highlight processes uniquely required for de novo hematopoietic stem cell generation, as these are the conditions that will need to be recreated for the successful production of blood stem cells in culture.

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“…To correlate our biologic findings with gene expression changes induced by reduced Erg activity or loss of Mpl signaling, we compared the published lists of differentially regulated genes in the LSK fraction of Erg ϩ/Mld2 mice 16 with those deregulated in the LSK fraction of Mpl Ϫ/Ϫ mice. 25 Of 240 genes differentially expressed in the LSK fraction of either Erg ϩ/Mld2 or Mpl Ϫ/Ϫ mice, only 2 were concordantly deregulated in both Erg ϩ/Mld2 and Mpl Ϫ/Ϫ LSK cells ( Figure 5). Furthermore, the expression changes undergone by differentially expressed genes in Mpl Ϫ/Ϫ and Erg ϩ/Mld2 LSK cells were generally uncorrelated, with no tendency to be in the same direction (P ϭ .3).…”

Section: Distinct Genetic Programs Are Regulated By Erg and Mpl Signamentioning

confidence: 99%

“…Previously published microarray data available at Array Expression (www.ebi.ac.uk/arrayexpress) under access number E-TABM-371 and E-TABM-1050 16,25 were analyzed in R (Version 2.10.0) using the limma (Version 2.8) package of the Bioconducor software project (www.bioconductor.org). 26 Each mutant was analyzed with its independent set of control wild-type mice.…”

Section: Microarray Analysismentioning

confidence: 99%

Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice

Loughran

Metcalf

et al. 2011

Blood

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Hematopoietic stem cells (HSCs) are rare residents of the bone marrow responsible for the lifelong production of blood cells. Regulation of the balance between HSC self-renewal and differentiation is central to hematopoiesis, allowing precisely regulated generation of mature blood cells at steady state and expanded production at times of rapid need, as well as maintaining ongoing stem cell capacity. Erg, a member of the Ets family of transcription factors, is deregulated in cancers; and although Erg is known to be required for regulation of adult HSCs, its precise role has not been defined. We show here that, although heterozygosity for functional Erg is sufficient for adequate steady-state HSC maintenance, Erg ؉/Mld2 mutant mice exhibit impaired HSC self-renewal after bone marrow transplantation or during recovery from myelotoxic stress. Moreover, although mice functionally compromised for either Erg or Mpl, the receptor for thrombopoietin, a key regulator of HSC quiescence, maintained sufficient HSC activity to sustain hematopoiesis, Mpl ؊/؊ Erg ؉/Mld2 compound mutant mice displayed exacerbated stem cell deficiencies and bone marrow failure. Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self-renewal at times of high HSC cycling. (Blood. 2011;118(9): 2454-2461) IntroductionAdult hematopoietic stem cells (HSCs) are a rare population of bone marrow cells responsible for the production of multiple functionally specialized lineages of blood cells. In addition to maintaining exquisitely regulated numbers of cells during the normal daily replacement of billions of aged or expended blood cells, HSCs are also critical for regeneration and maintenance of hematopoiesis in response to major hematologic stresses, such as after myelotoxic therapy or stem cell transplantation. Life-long maintenance of the blood cell system requires HSC self-renewal, a specialized cell division in which one or both daughter cells retain full long-term HSC pluripotency. Regulation of the appropriate balance between HSC self-renewal and differentiation is the essence of hematopoiesis, allowing production of sufficient effector blood cells while protecting sufficient pluripotential reserve capacity for future hematopoietic supply. Analysis of the effects of genetic mutation or gene dysregulation have defined diverse molecular regulators of physiologic and stress-induced HSC selfrenewal, including transcription factors, epigenetic regulators, cell cycle modulators, and cell extrinsic regulators and their intracellular signal transducers. 1,2 The E-twenty-six (ETS)-related gene (ERG, OMIM ID 165080) is a member of the ETS family of transcription factors. 3 A key role for ERG in cancer has emerged with the observation that up to 75% of prostate cancers are characterized by ERG deregulation. This commonly occurs via a chromosomal rearrangement that fuses the 5Ј untranslated region of the TMPRSS2 (androgen-regulated transmembrane protease, serine 2, OMIM ID 602060) gene with the 3Ј region of ERG, resulting in expression o...

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Regulation of hematopoietic stem cells by their mature progeny

Cited by 65 publications

References 45 publications

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development

Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice

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