Aryl hydrocarbon receptor in mesenchymal stromal cells: new frontiers in AhR biology

Abney, Kristopher K.; Galipeau, Jacques

doi:10.1111/febs.15599

Cited by 6 publications

(6 citation statements)

References 94 publications

(105 reference statements)

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“…These findings are in line with the negative impact of the AhR antagonist CH-223191 on osteogenesis and delayed bone healing in AhR −/− mice. 61,62 Interestingly, AhR knockdown also mitigated the inhibitory effect of Picoberin on osteoblast differentiation after 48 and 96 h (Figure 5C,D). These data strongly point toward AhR as the functional target of Picoberin during Hh-induced osteogenesis and reveal a tight regulation of AhR expression and signaling for proper osteoblast differentiation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

et al. 2022

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Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation. Global transcriptome and proteome profiling revealed the aryl hydrocarbon receptor (AhR) as the molecular target of this compound and identified a cross talk between Hh and AhR signaling during osteoblast differentiation.

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Section: ■ Results and Discussionmentioning

confidence: 99%

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

et al. 2022

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“…MSCs constitute a heterogenous population of cells that can differentiate into several mesodermal cell lineages such as chondrocytes, adipocytes, and osteoblasts (Abney & Galipeau 2021). The AhR is strongly expressed in MSCs (Huang et al 2022), and many independent reports indicate that AhR-mediated signaling inhibits MSC proliferation (Zhou et al 2017, Jia et al 2021, Huang et al 2022.…”

Section: Role Of Ahr In Mscsmentioning

confidence: 99%

“…MSCs play a role in a variety of biological processes including inflammation (Abney & Galipeau 2021), and the AhR is implicated in the anti-inflammatory effect of MSCs (Xu et al 2015). Mechanistically, after MSCs arrive to the site of injury, they induce a switch in macrophage phenotype from the proinflammatory M1 to the anti-inflammatory M2 (Cui et al 2020) and pharmacological inhibition of AhR by CH223191 reduced the polarization of macrophages from M1 to M2 phenotype and exacerbated inflammation (Cui et al 2020).…”

Section: Role Of Ahr In Mscsmentioning

confidence: 99%

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Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

Alhamad

Bensreti

Dorn

et al. 2022

Journal of Molecular Endocrinology

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The aryl hydrocarbon receptor (AhR) has been implicated in regulating skeletal progenitor cells and the activity of bone forming osteoblasts and bone resorbing osteoclasts, thereby impacting bone mass and the risk of skeletal fractures. The AhR also plays an important role in the immune system within the skeletal niche and the differentiation of mesenchymal stem cells into other cell lineages including chondrocytes and adipocytes. This transcription factor responds to environmental pollutants which can act as AhR ligands, initiating or interfering with various signaling cascades to mediate downstream effects, and also responds to endogenous ligands including tryptophan metabolites. This review comprehensively describes the reported roles of the AhR in skeletal cell biology, focusing on mesenchymal stem cells, osteoblasts, and osteoclasts, and discusses how AhR exhibits sexually dimorphic effects in bone. The molecular mechanisms mediating AhR’s downstream effects are highlighted to emphasize the potential importance of targeting this signaling cascade in skeletal disorders.

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“…Aside from the secretome and engulfment of MSCs, a proposed mechanism mediated by MSCs resulting in macrophage polarization, or macrophage phenotype “plasticity,” is by the activation of the aryl hydrocarbon receptor (AhR). This MSC receptor responds to environmental stimuli and contributes to both physiological cell development and immune regulation ( Abney and Galipeau, 2020 ). The AhR, when bound by ligands of environmental pollutants, translocates from the cytoplasm to the nucleus and facilitates AhR-related transcription of genes, which typically elicit immunotoxicological effects.…”

Section: Contact-dependent Communicationmentioning

confidence: 99%

Molecular Crosstalk Between Macrophages and Mesenchymal Stromal Cells

Stevens

Bowles

Yeago

et al. 2020

Front. Cell Dev. Biol.

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Mesenchymal stromal cells (MSCs) have been widely investigated for regenerative medicine applications, from treating various inflammatory diseases as a cell therapy to generating engineered tissue constructs. Numerous studies have evaluated the potential effects of MSCs following therapeutic administration. By responding to their surrounding microenvironment, MSCs may mediate immunomodulatory effects through various mechanisms that directly (i.e., contact-dependent) or indirectly (i.e., paracrine activity) alter the physiology of endogenous cells in various disease pathologies. More specifically, a pivotal crosstalk between MSCs and tissue-resident macrophages and monocytes (TMφ) has been elucidated using in vitro and in vivo preclinical studies. An improved understanding of this crosstalk could help elucidate potential mechanisms of action (MOAs) of therapeutically administered MSCs. TMφ, by nature of their remarkable functional plasticity and prevalence within the body, are uniquely positioned as critical modulators of the immune system – not only in maintaining homeostasis but also during pathogenesis. This has prompted further exploration into the cellular and molecular alterations to TMφ mediated by MSCs. In vitro assays and in vivo preclinical trials have identified key interactions mediated by MSCs that polarize the responses of TMφ from a pro-inflammatory (i.e., classical activation) to a more anti-inflammatory/reparative (i.e., alternative activation) phenotype and function. In this review, we describe physiological and pathological TMφ functions in response to various stimuli and discuss the evidence that suggest specific mechanisms through which MSCs may modulate TMφ phenotypes and functions, including paracrine interactions (e.g., secretome and extracellular vesicles), nanotube-mediated intercellular exchange, bioenergetics, and engulfment by macrophages. Continued efforts to elucidate this pivotal crosstalk may offer an improved understanding of the immunomodulatory capacity of MSCs and inform the development and testing of potential MOAs to support the therapeutic use of MSCs and MSC-derived products in various diseases.

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Aryl hydrocarbon receptor in mesenchymal stromal cells: new frontiers in AhR biology

Cited by 6 publications

References 94 publications

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

Molecular Crosstalk Between Macrophages and Mesenchymal Stromal Cells

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