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Gastrointestinal Fibroblasts Have Specialized, Diverse Transcriptional Phenotypes: A Comprehensive Gene Expression Analysis of Human Fibroblasts.

Higuchi Y, Kojima M, Ishii G, Aoyagi K, Sasaki H, Ochiai A - PLoS ONE (2015)

Bottom Line: The signature genes that discriminated GIFs from non-GIFs, SMFs from SPFs, and the fibroblasts of one organ from another organ consisted of genes associated with transcriptional regulation, signaling ligands, and extracellular matrix remodeling.In addition, the anatomical site- and organ-dependent diversity of GIFs was also discovered.These features of GIFs contribute to their specific physiological function and homeostatic maintenance, and create a functional diversity of the gastrointestinal tract.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.

ABSTRACT

Background: Fibroblasts are the principal stromal cells that exist in whole organs and play vital roles in many biological processes. Although the functional diversity of fibroblasts has been estimated, a comprehensive analysis of fibroblasts from the whole body has not been performed and their transcriptional diversity has not been sufficiently explored. The aim of this study was to elucidate the transcriptional diversity of human fibroblasts within the whole body.

Methods: Global gene expression analysis was performed on 63 human primary fibroblasts from 13 organs. Of these, 32 fibroblasts from gastrointestinal organs (gastrointestinal fibroblasts: GIFs) were obtained from a pair of 2 anatomical sites: the submucosal layer (submucosal fibroblasts: SMFs) and the subperitoneal layer (subperitoneal fibroblasts: SPFs). Using hierarchical clustering analysis, we elucidated identifiable subgroups of fibroblasts and analyzed the transcriptional character of each subgroup.

Results: In unsupervised clustering, 2 major clusters that separate GIFs and non-GIFs were observed. Organ- and anatomical site-dependent clusters within GIFs were also observed. The signature genes that discriminated GIFs from non-GIFs, SMFs from SPFs, and the fibroblasts of one organ from another organ consisted of genes associated with transcriptional regulation, signaling ligands, and extracellular matrix remodeling.

Conclusions: GIFs are characteristic fibroblasts with specific gene expressions from transcriptional regulation, signaling ligands, and extracellular matrix remodeling related genes. In addition, the anatomical site- and organ-dependent diversity of GIFs was also discovered. These features of GIFs contribute to their specific physiological function and homeostatic maintenance, and create a functional diversity of the gastrointestinal tract.

No MeSH data available.


Anatomical Site and Organ Signature Genes Discriminate the Topological Diversity of Gastrointestinal Fibroblasts.(A) Hierarchical clustering of the stomach, ileum, and colon fibroblasts, based on 585 probe sets that consisted of 498 anatomical site signature genes and 87 common organ signature genes, as shown in Figs 3 and 4. The bar indicates the positional information of the samples: upper bar indicates submucosal fibroblasts (red) or subperitoneal fibroblasts (blue), and the lower bar indicates stomach (gray), ileum (green), or colon (orange). (B-E) The validation study of the anatomical site and organ signature genes in independent fibroblasts samples. The mRNA expression of SPFs signature: MSX1 (B), SMFs signature: PITX1 (C), colon fibroblasts signature: HOXA10 (D), and stomach fibroblasts signature: HOXB8 (E) were calculated (n = 3).
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pone.0129241.g005: Anatomical Site and Organ Signature Genes Discriminate the Topological Diversity of Gastrointestinal Fibroblasts.(A) Hierarchical clustering of the stomach, ileum, and colon fibroblasts, based on 585 probe sets that consisted of 498 anatomical site signature genes and 87 common organ signature genes, as shown in Figs 3 and 4. The bar indicates the positional information of the samples: upper bar indicates submucosal fibroblasts (red) or subperitoneal fibroblasts (blue), and the lower bar indicates stomach (gray), ileum (green), or colon (orange). (B-E) The validation study of the anatomical site and organ signature genes in independent fibroblasts samples. The mRNA expression of SPFs signature: MSX1 (B), SMFs signature: PITX1 (C), colon fibroblasts signature: HOXA10 (D), and stomach fibroblasts signature: HOXB8 (E) were calculated (n = 3).

Mentions: We found that the diversity of stomach, ileum, and colon fibroblasts is explained by the anatomical site signature genes and common organ signature genes. To test the distinction ability of these signature genes, we united 87 probe sets of common organ signature genes and 498 probe sets of anatomical site signature genes, and performed hierarchical clustering. As a result, the dendrogram showed the cluster that separated the samples depended on both their anatomical site and organ (Fig 5A). Using qRT-PCR and immunofluorescence staining, we confirmed the mRNA and protein expression of the signature genes, paired-like homeodomain 1 (PITX1) in SMFs, MSX1 in SPFs, homeobox A10 (HOXA10) in colon fibroblasts, and homeobox B8 (HOXB8) in stomach fibroblasts in independent samples (Fig 5B–5E, S4 Fig and S5 Fig). These results indicate that the transcriptional diversity within GIFs was mainly discriminated by their 2 topological axes, which are anatomical site and gastrointestinal organ.


Gastrointestinal Fibroblasts Have Specialized, Diverse Transcriptional Phenotypes: A Comprehensive Gene Expression Analysis of Human Fibroblasts.

Higuchi Y, Kojima M, Ishii G, Aoyagi K, Sasaki H, Ochiai A - PLoS ONE (2015)

Anatomical Site and Organ Signature Genes Discriminate the Topological Diversity of Gastrointestinal Fibroblasts.(A) Hierarchical clustering of the stomach, ileum, and colon fibroblasts, based on 585 probe sets that consisted of 498 anatomical site signature genes and 87 common organ signature genes, as shown in Figs 3 and 4. The bar indicates the positional information of the samples: upper bar indicates submucosal fibroblasts (red) or subperitoneal fibroblasts (blue), and the lower bar indicates stomach (gray), ileum (green), or colon (orange). (B-E) The validation study of the anatomical site and organ signature genes in independent fibroblasts samples. The mRNA expression of SPFs signature: MSX1 (B), SMFs signature: PITX1 (C), colon fibroblasts signature: HOXA10 (D), and stomach fibroblasts signature: HOXB8 (E) were calculated (n = 3).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4457624&req=5

pone.0129241.g005: Anatomical Site and Organ Signature Genes Discriminate the Topological Diversity of Gastrointestinal Fibroblasts.(A) Hierarchical clustering of the stomach, ileum, and colon fibroblasts, based on 585 probe sets that consisted of 498 anatomical site signature genes and 87 common organ signature genes, as shown in Figs 3 and 4. The bar indicates the positional information of the samples: upper bar indicates submucosal fibroblasts (red) or subperitoneal fibroblasts (blue), and the lower bar indicates stomach (gray), ileum (green), or colon (orange). (B-E) The validation study of the anatomical site and organ signature genes in independent fibroblasts samples. The mRNA expression of SPFs signature: MSX1 (B), SMFs signature: PITX1 (C), colon fibroblasts signature: HOXA10 (D), and stomach fibroblasts signature: HOXB8 (E) were calculated (n = 3).
Mentions: We found that the diversity of stomach, ileum, and colon fibroblasts is explained by the anatomical site signature genes and common organ signature genes. To test the distinction ability of these signature genes, we united 87 probe sets of common organ signature genes and 498 probe sets of anatomical site signature genes, and performed hierarchical clustering. As a result, the dendrogram showed the cluster that separated the samples depended on both their anatomical site and organ (Fig 5A). Using qRT-PCR and immunofluorescence staining, we confirmed the mRNA and protein expression of the signature genes, paired-like homeodomain 1 (PITX1) in SMFs, MSX1 in SPFs, homeobox A10 (HOXA10) in colon fibroblasts, and homeobox B8 (HOXB8) in stomach fibroblasts in independent samples (Fig 5B–5E, S4 Fig and S5 Fig). These results indicate that the transcriptional diversity within GIFs was mainly discriminated by their 2 topological axes, which are anatomical site and gastrointestinal organ.

Bottom Line: The signature genes that discriminated GIFs from non-GIFs, SMFs from SPFs, and the fibroblasts of one organ from another organ consisted of genes associated with transcriptional regulation, signaling ligands, and extracellular matrix remodeling.In addition, the anatomical site- and organ-dependent diversity of GIFs was also discovered.These features of GIFs contribute to their specific physiological function and homeostatic maintenance, and create a functional diversity of the gastrointestinal tract.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.

ABSTRACT

Background: Fibroblasts are the principal stromal cells that exist in whole organs and play vital roles in many biological processes. Although the functional diversity of fibroblasts has been estimated, a comprehensive analysis of fibroblasts from the whole body has not been performed and their transcriptional diversity has not been sufficiently explored. The aim of this study was to elucidate the transcriptional diversity of human fibroblasts within the whole body.

Methods: Global gene expression analysis was performed on 63 human primary fibroblasts from 13 organs. Of these, 32 fibroblasts from gastrointestinal organs (gastrointestinal fibroblasts: GIFs) were obtained from a pair of 2 anatomical sites: the submucosal layer (submucosal fibroblasts: SMFs) and the subperitoneal layer (subperitoneal fibroblasts: SPFs). Using hierarchical clustering analysis, we elucidated identifiable subgroups of fibroblasts and analyzed the transcriptional character of each subgroup.

Results: In unsupervised clustering, 2 major clusters that separate GIFs and non-GIFs were observed. Organ- and anatomical site-dependent clusters within GIFs were also observed. The signature genes that discriminated GIFs from non-GIFs, SMFs from SPFs, and the fibroblasts of one organ from another organ consisted of genes associated with transcriptional regulation, signaling ligands, and extracellular matrix remodeling.

Conclusions: GIFs are characteristic fibroblasts with specific gene expressions from transcriptional regulation, signaling ligands, and extracellular matrix remodeling related genes. In addition, the anatomical site- and organ-dependent diversity of GIFs was also discovered. These features of GIFs contribute to their specific physiological function and homeostatic maintenance, and create a functional diversity of the gastrointestinal tract.

No MeSH data available.