Reticular Fibroblasts Expressing the Transcription Factor WT1 Define a Stromal Niche that Maintains and Replenishes Splenic Red Pulp Macrophages

Bellomo, Alicia; Mondor, Isabelle; Spinelli, Lionel; Lagueyrie, M.; Stewart, Benjamin J; Brouilly, Nicolas; Malissen, Bernard; Clatworthy, Menna R.; Bajénoff, Marc

doi:10.1016/j.immuni.2020.06.008

Cited by 75 publications

(109 citation statements)

References 101 publications

(115 reference statements)

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“…Cells within the Coch+ cluster corresponded to red pulp fibroblasts and alveolar fibroblasts, as determined by higher expression of Wt1, Csf1 (red pulp fibroblasts) and Npnt and Ces1d (alveolar fibroblasts) 34,39–41 relative to universal fibroblasts. This is consistent with observations showing that Wt1 -expressing red pulp fibroblasts maintain red pulp macrophage homeostasis via provision of Csf1 39 , though it is unclear if these mechanisms apply in the lung. The Cxcl12+ cluster was a mix of Lepr + mesenchymal stromal cells which express Lepr and Adipoq and mesenchymal-derived Emb+, Sp7+ osteolineage cells 21,42–44 , two cell types that are known to regulate hematopoietic niches in the bone microenvironment.…”

Section: Resultsmentioning

confidence: 98%

“…This approach suggested that the Ccl19+ cluster was composed of fibroblastic reticular cells, which regulate immune cell localization and function in secondary lymphoid organs 3 . Cells within the Coch+ cluster corresponded to red pulp fibroblasts and alveolar fibroblasts, as determined by higher expression of Wt1, Csf1 (red pulp fibroblasts) and Npnt and Ces1d (alveolar fibroblasts) 34,[39][40][41] relative to universal fibroblasts. This is consistent with observations showing that Wt1-expressing red pulp fibroblasts maintain red pulp macrophage homeostasis via provision of Csf1 39 , though it is unclear if these mechanisms apply in the lung.…”

Section: Cross-tissue Transcriptional Panorama Of Fibroblasts In Steamentioning

confidence: 98%

See 1 more Smart Citation

Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

Buechler¹,

Pradhan²,

Calviello³

et al. 2021

Preprint

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Fibroblasts are non-hematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and play key roles in fibrosis, cancer, autoimmunity and wound healing. Recent studies have described fibroblast heterogeneity within individual tissues. However, the field lacks a definition of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here, we integrated single-cell RNA transcriptomic data from ~150,000 fibroblast cells derived from 16 steady- and 11 perturbed-state mouse organs into fibroblast atlases. These data revealed two universal fibroblast cell subtypes, marked by expression of Pi16 or Col15a1, in all tissues; it also revealed discrete subsets of five specialized fibroblast subtypes in steady-state tissues and three activated fibroblast subtypes in perturbed or diseased tissues. These subsets were transcriptionally shaped by microenvironmental context rather than tissue-type alone. Inference of fibroblast lineage structure from the murine steady-state and perturbed-state fibroblast atlases suggested that specialized and activated subtypes are developmentally related to universal tissue-resident fibroblasts. Analysis of human samples revealed that fibroblast subtypes found in mice are conserved between species, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In sum, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution enabled us to define the organizing principles of the fibroblast lineage in health and disease.

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Section: Resultsmentioning

confidence: 98%

Section: Cross-tissue Transcriptional Panorama Of Fibroblasts In Steamentioning

confidence: 98%

Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

Buechler¹,

Pradhan²,

Calviello³

et al. 2021

Preprint

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show abstract

“…As discussed by van Esbroeck et al (65), this could be the case of Abhd6 DAG lipase activity. As another example, conditional deletion of colony stimulating factor 1 (Csf1) selectively in spleen red pulp fibroblasts dramatically altered red pulp macrophage content without any change in the level of circulating Csf1 (66). The same reason might also explain the small but nonsignificant increase of brain LPI observed in KO mice.…”

Section: Discussionmentioning

confidence: 99%

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Briand‐Mésange

Pons

Allart

et al. 2020

Journal of Biological Chemistry

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Endocannaboid signaling plays a regulatory role in various (neuro)biological functions. 2-Arachidonoyglycerol (2-AG) is the most abundant endocannabinoid, and while its canonical biosynthetic pathway involving phosphoinositide-specific phospholipase C and diacylglycerol lipase α is known, alternative pathways remain unsettled. Here, we characterize a non-canonical pathway implicating glycerophosphodiesterase 3 (GDE3, from GDPD2 gene). Human GDE3 expressed in HEK293T cell membranes catalyzed the conversion of lysophosphatidylinositol (LPI) into monoacylglycerol and inositol-1-phosphate. The enzyme was equally active against 1-acyl- and 2-acyl-LPI. When using 2-acyl LPI, where arachidonic acid is the predominant fatty acid, LC-MS analysis identified 2-AG as the main product of LPI hydrolysis by GDE3. Furthermore, inositol-1-phosphate release into the medium occurred upon addition of LPI to intact cells, suggesting that GDE3 is actually an ecto-lysophospholipase C. In cells expressing G-protein-coupled receptor GPR55, GDE3 abolished 1-acyl-LPI-induced signaling. In contrast, upon simultaneous expression of GDE3 and cannabinoid receptor CB2, 2-acyl-LPI evoked the same signal as that induced by 2-AG. These data strongly suggest that, beside simply degrading the GPR55 LPI ligand, GDE3 can act as a switch between GPR55 and CB2 signaling. Coincident with a major expression of both GDE3 and CB2 in spleen, spleens from transgenic mice lacking GDE3 displayed doubling of LPI content, compared to wild type mice. Decreased production of 2-AG in whole spleen was also observed, supporting the in vivo relevance of our findings. These data thus open a new research avenue in the field of endocannabinoid generation and reinforce the view of GPR55/LPI being genuine actors of endocannabinoid system.

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“…One possibility is that engulfment of dying erythrocytes, which both populations perform millions of times a day (24,44), provides the key defining source of heme. Alternatively, splenic red pulp macrophages are seeded in a WT1+ stromal network similar to that observed in Kupffer cells (45), which may synthesize and release heme that is subsequently imported via the heme transporter HCP1 (SLC46A1) (46,47).…”

Section: Metabolic Regulation Of Tissue-resident Macrophage Identitymentioning

confidence: 99%

“…Conversely, rapamycin-insensitive mTORC2 acts as a negative regulator of GATA6, and its suppression is required for peritoneal TRM differentiation (52). Given that WT1+ stromal cells are a major constituent in two unrelated tissue environments (45,50), it seems reasonable to conjecture that WT1+ stromal cells are a major non-cell-autonomous regulator of TRM metabolism. In support of this hypothesis, two independent studies observed that the liver also features WT1+ hepatic stellate cells that appear to be important regulators of liver fibrosis and scarring (53,54).…”

Section: Metabolic Regulation Of Tissue-resident Macrophage Identitymentioning

confidence: 99%

Immunometabolism of Tissue-Resident Macrophages – An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies

et al. 2021

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Tissue-resident macrophages exist in unique environments, or niches, that inform their identity and function. There is an emerging body of literature suggesting that the qualities of this environment, such as the types of cells and debris they eat, the intercellular interactions they form, and the length of time spent in residence, collectively what we call habitare, directly inform their metabolic state. In turn, a tissue-resident macrophage’s metabolic state can inform their function, including whether they resolve inflammation and protect the host from excessive perturbations of homeostasis. In this review, we summarize recent work that seeks to understand the metabolic requirements for tissue-resident macrophage identity and maintenance, for how they respond to inflammatory challenges, and for how they perform homeostatic functions or resolve inflammatory insults. We end with a discussion of the emerging technologies that are enabling, or will enable, in situ study of tissue-resident macrophage metabolism.

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Reticular Fibroblasts Expressing the Transcription Factor WT1 Define a Stromal Niche that Maintains and Replenishes Splenic Red Pulp Macrophages

Abstract: Highlights d RPMs are embedded in a meshwork of WT1, CSF1expressing RP fibroblasts d RP fibroblasts represent a unique subset of splenic stromal cells d RP-fibroblast-derived CSF1 controls homeostasis of RPMs d RP fibroblasts participate to the recruitment of monocytes

Cited by 75 publications

References 101 publications

Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Immunometabolism of Tissue-Resident Macrophages – An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies

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