Comparing development and regeneration in the submandibular gland highlights distinct mechanisms

Chatzeli, Lemonia; Teshima, Tathyane Harumi Nakajima; Hajihosseini, Mohammad K.; Gaete, Marcia; Proctor, Gordon; Tucker, Abigail S.

doi:10.1111/joa.13387

Cited by 7 publications

(6 citation statements)

References 69 publications

(157 reference statements)

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“…1E). We evaluated subpopulations expressing two growth factors with known importance in proacinar cell differentiation: Fgf2 (Hosseini et al, 2018) and Fgf10 (Chatzeli et al, 2021;Patel et al, 2007;Wells et al, 2013) (Fig. 1F).…”

Section: Scrna-seq Identification Of Multiple Salivary Gland Stromal ...mentioning

confidence: 99%

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

et al. 2022

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Stromal cells can direct differentiation of epithelial progenitor cells during organ development. FGF signaling is essential for submandibular salivary gland development. Through stromal fibroblast cells, FGF2 can indirectly regulate proacinar cell differentiation in organoids but the mechanisms are not understood. We performed scRNA-Seq and identified multiple stromal cell subsets, including Pdgfrα+ stromal subsets expressing both Fgf2 and Fgf10. When combined with epithelial progenitor cells in organoids, MACS-sorted PDGFRα+ cells promoted proacinar differentiation similarly to total stroma. Gene expression analysis revealed that FGF2 increases multiple stromal genes, including Bmp2 and Bmp7. Both BMP2 and BMP7 synergized with FGF2 stimulating proacinar differentiation, but not branching. However, stromal cells grown without FGF2 did not support proacinar organoid differentiation and instead differentiated into myofibroblasts. In organoids, TGFβ1 treatment stimulate myofibroblast differentiation and inhibited the epithelial progenitor cell's proacinar differentiation. Conversely, FGF2 reversed the TGFβ1's effects. We also demonstrated that adult salivary stromal cells were FGF2 responsive and could promote proacinar differentiation. These FGF2 signaling pathways may have applications in future regenerative therapies.

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Section: Scrna-seq Identification Of Multiple Salivary Gland Stromal ...mentioning

confidence: 99%

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

et al. 2022

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“…1E). We evaluated subpopulations expressing two growth factors with known importance in proacinar differentiation, Fgf2 (Hosseini et al, 2018) and Fgf10 (Chatzeli et al, 2021; Patel et al, 2007; Wells et al, 2013) (Fig. 1F).…”

Section: Resultsmentioning

confidence: 99%

“…Using organoids, we determined which subpopulations direct proacinar differentiation. The neural crest markers’ (Morikawa et al, 2009) co-expression with proacinar signaling growth factors (Chatzeli et al, 2021; Hosseini et al, 2018; Patel et al, 2007; Wells et al, 2013) suggests that PDGFRα + cells are potentially key contributors. Others have highlighted a theme where PDGFRα stromal expression aligns with functional dexterity (Contreras et al, 2019; Li et al, 2018; Santini et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

PDFGRα⁺ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling

Moskwa

Mahmood

Nelson

et al. 2021

Preprint

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3.0AbstractStromal cells can direct epithelial differentiation during organ development; however, these pathways remain poorly defined. FGF signaling is essential for submandibular salivary gland development, and FGF2 can regulate proacinar cell differentiation in organoids through autocrine signaling in stromal cells. We performed scRNA Seq and identified stromal cell subsets expressing Fgf2 and Fgf10 that also express Pdgfrα. When combined with epithelial cells in organoids, MACS-sorted PDGFRα+ cells sufficiently promoted proacinar differentiation. Gene expression analysis revealed FGF2 activates the gene Bmp7 in the stroma. BMP7 could replace stromalsignaling and stimulate epithelial acinar differentiation but not branching. However, in the absence of FGF2, pathway analysis revealed that the stromal cells differentiated into myofibroblasts. Myofibroblast differentiation was induced when we treated organoids with TGFβ1, which also prevented proacinar differentiation. Conversely, FGF2 reversed TGFβ’s effects. Dissecting pathways driving acinar differentiation will facilitate development of regenerative therapies.2.0Summary StatementEmbryonic salivary glands contain multiple stromal cell populations. FGF2 maintains the stromal Pdgfrα+ population in-vitro. The PDGFRα+ stromal cells drive early epithelial secretory cell differentiation using BMP7.

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“…Developmental biologists have extensively studied branching morphogenesis, which explores the regulation of tree-like structures with thousands of branches. 79 The intrinsic contribution of a genetically encoded developmental program and the influence of environmental factors (such as morphogens, forces, and cell contacts) have been investigated in rodent models for salivary glands 53 , 80 and lacrimal glands. 81 , 82 However, apart from a century-old study, 83 such information is unavailable for human embryos.…”

Section: Discussionmentioning

confidence: 99%

A tridimensional atlas of the developing human head

Blain,

Couly,

Shotar

et al. 2023

Cell

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Comparing development and regeneration in the submandibular gland highlights distinct mechanisms

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 69 publications

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

PDFGRα⁺ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling

A tridimensional atlas of the developing human head

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Comparing development and regeneration in the submandibular gland highlights distinct mechanisms

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 69 publications

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

Single-cell RNA sequencing reveals PDGFRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids

PDFGRα+ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling

A tridimensional atlas of the developing human head

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Product

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PDFGRα⁺ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling