Canonical Wnt Signaling Regulates Hematopoiesis in a Dosage-Dependent Fashion

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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“…3B-G). HSCs function is regulated by the proximity and dose of Wnt signaling activity [19,44] (Fig. 6A).…”

Section: Deficiency Of Osteoblastic Wls Does Not Affect Hscs Maintenamentioning

confidence: 99%

“…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].…”

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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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“…19,20 The Wnt signaling pathways have been implicated as the signaling cascades involved in the regulation of hematopoietic stem cell (HSC) function and other stages during hematopoiesis. 21,22 Hematopoiesis proceeds in a stepwise manner from primordial long-term (LT)-HSCs that give rise to short-term (ST)-HSCs; in turn, (ST)-HSC can differentiate into a multipotent progenitor (MPP) population. 23 The canonical Wnt signaling pathway has been demonstrated to regulate the differentiation of HSC, myeloid precursors, and T lymphoid precursors during hematopoiesis in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…23 The canonical Wnt signaling pathway has been demonstrated to regulate the differentiation of HSC, myeloid precursors, and T lymphoid precursors during hematopoiesis in a dose-dependent manner. 21 Mild, intermediate, and intermediate-high levels of canonical Wnt pathway activation facilitate HSC function, myeloid development, and early T-cell development, respectively. 21 However, the non-canonical Wnt pathway was reported to inhibit canonical Wnt signaling in HSC and increased the numbers of short-term (ST-HSC) and long-term HSC (LT-HSC) populations by maintaining HSC in a quiescent G0 state.…”

Section: Introductionmentioning

confidence: 99%

The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

Xiao

Zhou

et al. 2015

Cell Mol Immunol

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The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a 2 CD8a 1 conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3 1 lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging. Cellular & Molecular Immunology

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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]. Soluble Wnt proteins, including Wnt3a and Wnt5a, support mouse and human HSC activity as determined by repopulation assays [57,58].…”

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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Canonical Wnt Signaling Regulates Hematopoiesis in a Dosage-Dependent Fashion

Cited by 295 publications

References 69 publications

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

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

The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

Ex vivo expansion of hematopoietic stem cells

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