Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells

Zhu, Jiang; Garrett, Russell; Jung, Younghun; Zhang, Yi; Kim, Nacksung; Wang, Jingcheng; Joe, Gerard; Hexner, Elizabeth O.; Choi, Yongwon; Taichman, Russell S.; Emerson, Stephen G.

doi:10.1182/blood-2006-08-041384

Cited by 339 publications

(344 citation statements)

References 24 publications

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“…Furthermore, reduced marrow IL-6 mRNA expression in Prg4 mutant mice may contribute to decreased frequency of B-lymphocytic cells, because IL-6 supports physiological B-lymphopoiesis. 28,53,54 Similar to Prg4 mutant mice, mice with an osteoprogenitor cell G s ␣ deficiency (a downstream mediator of the PPR) have decreased peripheral blood and marrow B-lymphocytic cells, 55 suggesting that osteoblast cell signaling also could play a role in Prg4 mutant mice. The unexpected finding that PTH induced normalization of peripheral blood neutrophils and marrow B-lymphocytic cells in Prg4 mutant mice to wild-type levels may be associated with the PTH-induced increase in marrow SDF-1 protein in Prg4 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa varapericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4 ؊/؊ mutant and Prg4 ؉/؉ wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220 ؉ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin ؊ Sca-1 ؉ c-Kit ؉ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTHstimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

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Section: Discussionmentioning

confidence: 99%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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“…BM osteoblasts were also shown to promote B-cell differentiation of murine hematopoietic progenitors in culture and depletion of BM osteoblasts in Col2.3D-TK mice resulted in a loss of pre-B-cell content in vivo. 22 The function of BM osteoblasts in regulating HSC fate was first suggested by Taichman et al, 23 who showed that in vitro culture of human BM CD34 þ cells with human osteoblasts supported a 3-4-fold expansion of long-term culture-initiating cells in vitro. More recently, the function of the BM osteoblast in regulating HSC pool size was demonstrated by Calvi et al, 4 who showed that activation of the parathyroid hormone/parathyroid hormone receptor in vivo increased BM osteoblast and trabecular bone content, yielding a significant increase in BM HSC numbers.…”

Section: Concept Of the Hematopoietic Stem Cell (Hsc) Nichementioning

confidence: 99%

“…9,14 Role of the BM osteoblast With advances in mouse genetics and microscopy, the function of the BM osteoblast in regulating hematopoiesis and HSC homeostasis has been demonstrated. 4,5,14,[21][22][23][24] Human osteoblasts were shown by Taichman and Emerson 21 to regulate the myeloid differentiation of human CD34 þ progenitor cells in culture via the production of granulocyte colony stimulating factor. BM osteoblasts were also shown to promote B-cell differentiation of murine hematopoietic progenitors in culture and depletion of BM osteoblasts in Col2.3D-TK mice resulted in a loss of pre-B-cell content in vivo.…”

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confidence: 99%

The vascular niche: home for normal and malignant hematopoietic stem cells

2011

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Hematopoietic stem cells (HSCs) are uniquely capable of selfrenewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niches' wherein HSCs reside. HSCs have been shown to reside in close association with bone marrow (BM) osteoblasts in the endosteal niche and also in proximity to BM sinusoidal vessels. An unresolved question surrounds whether the endosteal and vascular niches provide synchronous or redundant regulation of HSC fate or whether these niches provide wholly unique regulatory functions. Furthermore, while some aspects of the mechanisms through which osteoblasts regulate HSC fate have been defined, the mechanisms through which the vascular niche regulates HSC fate remain obscure. Here, we summarize the anatomic and functional basis supporting the concept of an HSC vascular niche as well as the precise function of endothelial cells, perivascular cells and stromal cells within the niche in regulating HSC fate. Lastly, we will highlight the role of the vascular niche in regulating leukemic stem cell fate in vivo. Leukemia (2012) Concept of the hematopoietic stem cell (HSC) nicheThe concept of an instructive role for the bone marrow (BM) microenvironment in regulating hematopoietic cell fate was introduced at least 50 years ago and has been validated over the past decade. 1-9 It has long been postulated that HSCs reside in specialized niches within the adult BM. [8][9][10][11][12][13][14] In addition to HSCs and their progeny, the BM comprises a rich network of osteoblasts, mesenchymal stem cells (MSCs), neuronal cells, adipocytes, sinusoidal vessels and perivascular reticular cells (Figure 1). Recently, genetic knockout studies have begun to demonstrate the functional role of specific cells within the BM microenvironment in regulating hematopoiesis. [3][4][5]7,[15][16][17][18][19][20] Interestingly, certain niches within the BM may uniquely regulate HSC homeostasis in vivo while other niches may be more relevant to HSC regeneration following injury. However, it remains unknown whether there is meaningful 'cross-talk' between distinct microenvironmental cells in regulating HSC fate in vivo. Interestingly, as early as 1961, Fliedner et al. 9 postulated that the recovery of hematopoiesis in rats following 1000 cGy total body irradiation (TBI) required the recovery of an intact vasculature. Similarly, McClugage et al. 14 used a window chamber to visualize dynamic changes in tibial BM cellularity and architecture in live rabbits. Interestingly, both studies suggested a strong association between vasculogenesis in the BM and the hematopoietic response to stress or injury. 9,14 Role of the BM osteoblast With advances in mouse genetics and microscopy, the function of the BM osteoblast in regulating hematopoiesis and HSC homeostasis has been demonstrated. 4,5,14,[21][22][23][24] Human osteoblasts were shown by Taichma...

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“…Osteoblasts also support B-cell commitment and differentiation [22][23][24]. However, the function of Wnt signaling in osteoblastsupported B-cell development remains controversial.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment and differentiation [22][23][24]. However, the function of Wnt signaling in osteoblastsupported B-cell development remains controversial.…”

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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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Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells

Abstract: Early B lymphopoiesis in mammals is

Cited by 339 publications

References 24 publications

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

The vascular niche: home for normal and malignant hematopoietic stem cells

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

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