Apc regulates the function of hematopoietic stem cells largely through β-catenin–dependent mechanisms

Li, Wenshu; Hou, Yu; Ming, Ming; Liu, Yu; Seba, A.; Qian, Zhijian

doi:10.1182/blood-2012-12-473470

Cited by 14 publications

(13 citation statements)

References 49 publications

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“…Of note, inhibition of β‐Cat/TCF with iCRT3 also reduced cell growth in SFM cultures which is consistent with previous studies linking β‐Cat to hematopoietic stem and progenitor cell proliferation (Fig. I) . In summary, the IGF‐1R and β‐Cat/TCF axis appears to mediate the bulk of the growth‐promoting activities of osteoblasts’ paracrine factors on hematopoietic progenitors.…”

Section: Resultssupporting

confidence: 90%

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

et al. 2018

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Ex vivo expansion of hematopoietic stem cell (HSCs) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood transplantation. Serumfree medium conditioned with osteoblasts (i.e., osteoblast-conditioned medium [OCM]) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets in mice transplanted with OCM-expanded progenitors. Herein, we characterized the cellular and molecular mechanisms responsible for these osteoblast-derived properties. Limiting dilution transplantation assays revealed that osteoblasts secrete soluble factors that synergize with exogenously added cytokines to promote the production of progenitors with short-term platelet engraftment activities, and to a lesser extent with long-term platelet engraftment activities. OCM also modulated the expression repertoire of cell-surface receptors implicated in the trafficking of HSC and progenitors to the bone marrow. Furthermore, OCM contains growth factors with prosurvival and proliferation activities that synergized with stem cell factor. Insulin-like growth factor (IGF)-2 was found to be present at higher levels in OCM than in control medium conditioned with MSC. Inhibition of the IGF-1 receptor, which conveys IGF-2 0 intracellular signaling, largely abolished the growth-promoting activity of OCM on immature CD34 + subsets and progenitors in OCM cultures. Finally, IGF-1R effects appear to be mediated in part by the coactivator β-catenin. In summary, these results provide new insights into the paracrine regulatory activities of osteoblasts on HSC, and how these can be used to modulate the engraftment properties of human HSC and progenitors expanded in culture. STEM CELLS 2019;37:345-356 SIGNIFICANCE STATEMENTOsteoblasts are one of many different cell type implicated in the regulation of hematopoiesis through various mechanism including the release of paracrine factors such as growth factors, chemokines and extracellular matrix proteins. It has been shown that these factors strongly modulate the growth of umbilical cord blood stem and progenitor cells through activation of insulin-like growth factor-1 receptor and subsequent activation of the transcriptional activation complex β-catenin/TCF. Osteoblasts also modulated the expression repertoire of cell-surface receptors implicated in the homing of progenitors to the bone marrow. Altogether, these properties significantly enhanced the platelet engrafting activity of progenitors produced in cultures.

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Section: Resultssupporting

confidence: 90%

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

et al. 2018

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“…The deletion of Apc or β-catenin was induced by pI-pC injection as we previously described(18). We monitored cohorts of mice for up to 8 months by CBC analysis monthly.…”

Section: Resultsmentioning

confidence: 99%

“…showed that only slightly increased levels of canonical Wnt signaling have a positive effect on HSC repopulation capacity(45). Our recent studies showed that Apc function in hematopoietic stem/progenitor cells is largely dependent on β-catenin(18). Here, we provide additional evidence that reduced doses of β-catenin by heterozygous deletion is sufficient to reverse Apc-heterozygous-induced expansion of HSCs as well as the functional defects of Apc haplo-insufficient HSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of Apc or β-catenin was induced by 3 doses of intraperitoneal (i.p.) injections of 6-10 μg polyI–polyC (pI-pC; GE Healthcare) per gram of body weight, and was confirmed by polymerase chain reaction (PCR) analysis as previously described (10,18). …”

Section: Methodsmentioning

confidence: 99%

“…We have shown that APC regulates the function of hematopoietic stem/progenitor cells largely through a β-catenin dependent mechanism(18). In the present study, we have extended our efforts to evaluate the possibility that targeting β-catenin affords a potential new therapeutic approach for the treatment of del(5q) patients.…”

Section: Introductionmentioning

confidence: 99%

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β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Sheng

et al. 2017

Cancer Research

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Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the pre-leukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells (HSC) and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q).

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Extracellular Adenosine (eAdo) - A2B Receptor Axis Inhibits in Nlrp3 Inflammasome-dependent Manner Trafficking of Hematopoietic Stem/progenitor Cells

Thapa

Abdelbaset‐Ismail

Chumak

et al. 2022

Stem Cell Rev and Rep

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We postulated that mobilization, homing, and engraftment of hematopoietic stem/progenitor cells (HSCPs) is facilitated by a state of sterile inflammation induced in bone marrow (BM) after administration of pro-mobilizing drugs or in response to pre-transplant myeloablative conditioning. An important role in this phenomenon plays purinergic signaling that by the release of extracellular adenosine triphosphate (eATP) activates in HSPCs and in cells in the hematopoietic microenvironment an intracellular pattern recognition receptor (PPR) known as Nlrp3 inflammasome. We reported recently that its deficiency results in defective trafficking of HSPCs. Moreover, it is known that eATP after release into extracellular space is processed by cell surface expressed ectonucleotidases CD39 and CD73 to extracellular adenosine (eAdo) that in contrast to eATP shows an anti-inflammatory effect. Based on data that the state of sterile inflammation promotes trafficking of HSPCs, and since eAdo is endowed with anti-inflammatory properties we become interested in how eAdo will affect the mobilization, homing, and engraftment of HSPCs and which of eAdo receptors are involved in these processes. As expected, eAdo impaired HSPCs trafficking and this occurred in autocrine- and paracrine-dependent manner by direct stimulation of these cells or by affecting cells in the BM microenvironment. We report herein for the first time that this defect is mediated by activation of the A2B receptor and a specific inhibitor of this receptor improves eAdo-aggravated trafficking of HSPCs. To explain this at the molecular level eAdo-A2B receptor interaction upregulates in HSPCs in NF-kB-, NRF2- and cAMP-dependent manner heme oxygenase-1 (HO-1), that is Nlrp3 inflammasome inhibitor. This corroborated with our analysis of proteomics signature in murine HSPCs exposed to eAdo that revealed that A2B inhibition promotes cell migration and proliferation. Based on this we postulate that blockage of A2B receptor may accelerate the mobilization of HSPCs as well as their hematopoietic reconstitution and this approach could be potentially considered in the future to be tested in the clinic. Graphical Abstract

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Apc regulates the function of hematopoietic stem cells largely through β-catenin–dependent mechanisms

Cited by 14 publications

References 49 publications

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Extracellular Adenosine (eAdo) - A2B Receptor Axis Inhibits in Nlrp3 Inflammasome-dependent Manner Trafficking of Hematopoietic Stem/progenitor Cells

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