Wnt Signaling in the Niche Enforces Hematopoietic Stem Cell Quiescence and Is Necessary to Preserve Self-Renewal In Vivo

Fleming, Heather E.; Janzen, Viktor; Celso, Cristina Lo; Guo, Jun; Leahy, K.; Kronenberg, Henry M.; Scadden, David T.

doi:10.1016/j.stem.2008.01.003

Cited by 447 publications

(421 citation statements)

References 56 publications

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“…Such discrepancies may in part be due to heterogeneity among cohorts of aged mice, or the sensitivity of different methods used to detect p16 Ink4a expression. Interestingly, Bondar and Medzhitov (2010) elegantly demonstrated that cell competition exists in regulated by a number of other BM niche-associated factors, including TPO, Wnt, and SDF-1 (Qian et al, 2007;Fleming et al, 2008;Nie et al, 2008). Collectively, these data indicate that multiple signaling mechanisms activated by developmental pathways and environmental factors may converge upon the regulation of CKI expression, which in turn might contribute to the prolonged passage of HSCs through the G 1 phase of the cell cycle.…”

Section: Cell-extrinsic Mechanisms Regulating Hsc Quiescencementioning

confidence: 95%

“…Notably, TGF- and Notch ligands up-regulate CXCR4, and this may account for some of their quiescenceenforcing activity (Franitza et al, 2002). On the other hand, activation of the Wnt and Hh pathways is associated with increased expression of cyclin D1 in HSCs, although Wnt signaling is typically associated with maintenance of HSC quiescence and self-renewal activity (Fleming et al, 2008;Merchant et al, 2010). It may be that signaling through these pathways helps to maintain basal expression of cyclin D1 in quiescent HSCs (Passegué et al, 2005).…”

Section: Cell-extrinsic Mechanisms Regulating Hsc Quiescencementioning

confidence: 99%

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Cell cycle regulation in hematopoietic stem cells

Pietras¹,

Warr²,

Passegué³

2011

J Exp Med

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Section: Cell-extrinsic Mechanisms Regulating Hsc Quiescencementioning

confidence: 95%

Section: Cell-extrinsic Mechanisms Regulating Hsc Quiescencementioning

confidence: 99%

Cell cycle regulation in hematopoietic stem cells

Pietras¹,

Warr²,

Passegué³

2011

J Exp Med

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“…Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work.…”

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confidence: 99%

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

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Osteoblasts and perivascular stromal cells constitute essential niches for HSC selfrenewal and maintenance in the bone marrow. Wnt signaling is important to maintain HSC integrity. However, the paracrine role of Wnt proteins in osteoblasts-supported HSC maintenance and differentiation remains unclear. Here, we investigated hematopoiesis in mice with Wntless (Wls) deficiency in osteoblasts or Nestin-positive mesenchymal progenitor cells, which presumptively block Wnt secretion in osteoblasts. We detected defective B-cell lymphopoiesis and abnormal T-cell infiltration in the bone marrow of Wls mutant mice. Notably, no impact on HSC frequency and repopulation in the bone marrow was observed with the loss of osteoblastic Wls. Our findings revealed a supportive role of Wnts in osteoblasts-regulated B-cell lymphopoiesis. They also suggest a preferential niche role of osteoblastic Wnts for lymphoid cells rather than HSCs, providing new clues for the molecular nature of distinct niches occupied by different hematopoietic cells.Keywords: B cell r HSC maintenance r Osteoblast r T-cell infiltration r Wntless Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCs that periodically generate all hematopoietic lineages are mostly stored in vascular or endosteal niches in the bone marrow [1]. Vascular niches consist of sinusoidal endothelium cells [2][3][4] whereas endosteal niches are mainly composed of osteoblasts [5,6]. These niche cells are important to regulate HSCs self-renewal and maintenance. Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11]. β-Catenin is the key and obligatory mediator of canonical Wnt signaling. Stabilized β-catenin expression expands the pool of HSCs and leads to deficiency in HSCs repopulation capacity [12,13]. Conversely, deletion of β-catenin or Wnt3a leads to defective HSCs long-term maintenance [14,15]. Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work. regulate HSCs self-renewal in a dosage-dependent manner [19]. In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment an...

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“…Wnt signaling is involved in HSC regulation (reviewed in [59,123]), and Wnt signaling was reported to maintain HSC in a quiescent status in vivo [124]. The effects of Wnt signaling are dosage and context dependent: low Wnt doses result in expansion of HSCs, whereas high doses cause exhaustion [125].…”

Section: Wnts and Glycogen Synthase Kinase 3 (Gsk-3) Inhibitormentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. ex vivo expansion, hematopoietic stem cells, niche, signal transduction, cord blood, transplantation, SCID-repopulating cell, genome editing, CRISPR/Cas9 Citation:Xie JJ, Zhang CC. Ex vivo expansion of hematopoietic stem cells.

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Wnt Signaling in the Niche Enforces Hematopoietic Stem Cell Quiescence and Is Necessary to Preserve Self-Renewal In Vivo

Cited by 447 publications

References 56 publications

Cell cycle regulation in hematopoietic stem cells

Cell cycle regulation in hematopoietic stem cells

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

Ex vivo expansion of hematopoietic stem cells

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