Wnt-5A/B Signaling in Hematopoiesis throughout Life

Rezende, Marina Mastelaro de; Justo, Giselle Z.; Paredes‐Gamero, Edgar Julian; Gosens, Reinoud

doi:10.3390/cells9081801

Cited by 13 publications

(11 citation statements)

References 137 publications

(217 reference statements)

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“…This conclusion is supported by the observation that Wnt5 DKO resulted in increased hematopoiesis in the spleens and reduced hematopoiesis in the bone marrow of DSS-treated mice. WNT5A has been implicated in bone marrow hematopoiesis and myelopoiesis, which are largely consistent with the bone marrow phenotypes of Wnt5 DKO [14,50,51]. The strong effect of Wnt5 DKO on EMH is unexpected.…”

Section: Discussionsupporting

confidence: 55%

“…Wingless-type MMTV integration site family member 5 (WNT5) consists of two members, WNT5A and WNT5B, which share 90% amino acid sequence identity [13]. These WNT5 proteins are involved in diverse physiological and pathological processes, including stem cell self-renewal, cell proliferation, differentiation, migration, adhesion, and polarity [14][15][16]. Wnt5a gene knockout (KO) causes embryonic lethality with significant development defects in mice, whereas Wnt5b KO mice show no obvious phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Luan

Wang

et al. 2023

Preprint

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WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout of Wnt5a and Wnt5b (Wnt5 DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+ T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences between Wnt5 DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+ T cell GZMB expression in the Wnt5 DKO mice. In addition, neutrophils from the Wnt5 DKO colitic mice exert stronger suppression of CD8+ T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treated Wnt5 DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Luan

Wang

et al. 2023

Preprint

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“…Our analysis on previously published data sets on human synovial membrane samples [ 50 ] confirmed that Wnt5A is overexpressed in RA samples (Additional file 1 : Figure S1). It was shown that the Wnt signaling plays critical role in immune cell regulation [ 51 – 53 ]. Additionally, DNA methylation data of human RA samples available on epigenome-wide association study (EWAS) datahub established that the level of CpG island DNA methylation was decreased during RA condition on the Wnt5A gene (Additional file 2 : Figure S2).…”

Section: Discussionmentioning

confidence: 99%

SETD2-mediated epigenetic regulation of noncanonical Wnt5A during osteoclastogenesis

et al. 2021

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To define the role of SETD2 in the WNT5a signaling in the context of osteoclastogenesis, we exploited two different models: in vitro osteoclast differentiation, and K/BxN serum-induced arthritis model. We found that SETD2 and WNT5a were upregulated during osteoclast differentiation and after induction of arthritis. Using gain- and loss-of-function approaches in the myeloid cell, we confirmed that SETD2 regulated the osteoclast markers, and WNT5a via modulating active histone marks by enriching H3K36me3, and by reducing repressive H3K27me3 mark. Additionally, during osteoclastic differentiation, the transcription of Wnt5a was also associated with the active histone H3K9 and H4K8 acetylations. Mechanistically, SETD2 directed induction of NF-κβ expression facilitated the recruitment of H3K9Ac and H4K8Ac around the TSS region of the Wnt5a gene, thereby, assisting osteoclast differentiation. Together these findings for the first time revealed that SETD2 mediated epigenetic regulation of Wnt5a plays a critical role in osteoclastogenesis and induced arthritis. Graphic abstract Model for the Role of SETD2 dependent regulation of osteoclastic differentiation. A In monocyte cells SETD2-dependent H3K36 trimethylation help to create open chromatin region along with active enhancer mark, H3K27Ac. This chromatin state facilitated the loss of a suppressive H3K27me3 mark. B Additionally, SETD2 mediated induction of NF-κβ expression leads to the recruitment of histone acetyl transferases, P300/PCAF, to the Wnt5a gene and establish H3K9Ac and H4K8Ac marks. Along with other activation marks, these acetylation marks help in Wnt5a transcription which leads to osteoclastogenesis.

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“…This effect was also seen for normal hematopoietic cells, where the pharmacological elimination of senescent hematopoietic stem cells counteracted the aging-dependent reduction in the regenerative potential of hematopoietic stem cells [46,47]. Furthermore, signaling through several intracellular pathways seems to be altered during aging due to intrinsic mechanisms, e.g., TGF1β, Notch, NFκB and Wnt signaling [24,[48][49][50][51]. Both the induction of senescence with an altered secretory profile and the altered intracellular signaling downstream to cell surface receptors may represent combined direct and indirect effects on hematopoiesis [12,14], including the effect of increased senescence on aging with altered mediator secretion and thereby the modulation of autocrine/paracrine circuits (Figure 1) [2,9].…”

Section: Senescence and Intracellular Signalingmentioning

confidence: 99%

Hematopoiesis, Inflammation and Aging—The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals

Bruserud

Reikvam

2022

JCM

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Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.

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Wnt-5A/B Signaling in Hematopoiesis throughout Life

Cited by 13 publications

References 137 publications

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

SETD2-mediated epigenetic regulation of noncanonical Wnt5A during osteoclastogenesis

Hematopoiesis, Inflammation and Aging—The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals

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