Abstract:SummaryTo understand organ function, it is important to have an inventory of its cell types and of their corresponding marker genes. This is a particularly challenging task for human tissues like the pancreas, because reliable markers are limited. Hence, transcriptome-wide studies are typically done on pooled islets of Langerhans, obscuring contributions from rare cell types and of potential subpopulations. To overcome this challenge, we developed an automated platform that uses FACS, robotics, and the CEL-Seq… Show more
“…These data confirm the striking differences between species as previously reported for the human and murine alpha- and beta-enriched genes [12, 21]. Importantly, many of the conserved alpha- and beta-specific genes identified in the present study were also recently highlighted as enriched in these endocrine cell types in several single cell RNA-seq studies [19–21] (Additional file 14: Table S8 (beta cells) and Additional file 15: Table S9 (alpha cells) for comparison).Fig. 7Identification of genes with conserved enriched expression in alpha and beta cells.…”
BackgroundDefining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types.ResultsIn this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan-endocrine and exocrine cells. These data suggest that the identity of the alpha and beta cells relies on a few key factors, corroborating numerous examples of inter-conversion between these two endocrine cell subtypes.ConclusionThis study highlights both evolutionary conserved and species-specific features that will help to unveil universal and fundamental regulatory pathways as well as pathways specific to human and laboratory animal models such as mouse and zebrafish.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0362-x) contains supplementary material, which is available to authorized users.
“…These data confirm the striking differences between species as previously reported for the human and murine alpha- and beta-enriched genes [12, 21]. Importantly, many of the conserved alpha- and beta-specific genes identified in the present study were also recently highlighted as enriched in these endocrine cell types in several single cell RNA-seq studies [19–21] (Additional file 14: Table S8 (beta cells) and Additional file 15: Table S9 (alpha cells) for comparison).Fig. 7Identification of genes with conserved enriched expression in alpha and beta cells.…”
BackgroundDefining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types.ResultsIn this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan-endocrine and exocrine cells. These data suggest that the identity of the alpha and beta cells relies on a few key factors, corroborating numerous examples of inter-conversion between these two endocrine cell subtypes.ConclusionThis study highlights both evolutionary conserved and species-specific features that will help to unveil universal and fundamental regulatory pathways as well as pathways specific to human and laboratory animal models such as mouse and zebrafish.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0362-x) contains supplementary material, which is available to authorized users.
“…Three research groups have described heterogeneity in the beta cell population with particular gene signatures driving such differences (Baron et al, 2016; Muraro et al, 2016; Segerstolpe et al, 2016). However, Xin et al (2016b) were not able to detect such diverse cell types.…”
The pancreatic beta cell functions as a key regulator of blood glucose levels by integrating a variety of signals in response to changing metabolic demands. Variations in beta cell identity that translate into functionally different subpopulations represent an interesting mechanism to allow beta cells to efficiently respond to diverse physiological and pathophysiological conditions. Recently, there is emerging evidence that morphological and functional differences between beta cells exist. Furthermore, the ability of novel single cell technologies to characterize the molecular identity of individual beta cells has created a new era in the beta cell field. These studies are providing important novel information about the origin of beta cell heterogeneity, the type and proportions of the different beta cell subpopulations, as well as their intrinsic properties. Furthermore, characterization of different beta cell subpopulations that could variably offer protection from or drive progression of diabetes has important clinical implications in diabetes prevention, beta cell regeneration and stem cell treatments. In this review, we will assess the evidence that supports the existence of heterogeneous populations of beta cells and the factors that could influence their formation. We will also address novel studies using islet single cell analysis that have provided important information toward understanding beta cell heterogeneity and discuss the caveats that may be associated with these new technologies.
“…For example, these studies revealed that delta cells uniquely express appetite-suppressing leptin ( LEPR ) and appetite-stimulating ghrelin ( GHSR ) hormone receptors [75,79,80], implicating them as the integrators and regulators of these pathways in the islet. GHSR functionality has been demonstrated in both human and mouse delta cells [70].…”
“…GHSR functionality has been demonstrated in both human and mouse delta cells [70]. LEPR expression is unique to human delta cells, suggesting that these cells may uniquely mediate the leptin response in human islets [70,75,76,79,80] (Figure 2). Expression of genes associated with congenital hyperinsulinemia (CHI) ( UCP2, HADH ) in delta cells further implicates this cell type in the molecular genetics of CHI [75].…”
“…Expression of genes associated with congenital hyperinsulinemia (CHI) ( UCP2, HADH ) in delta cells further implicates this cell type in the molecular genetics of CHI [75]. PP/gamma cell transcriptomes exhibited enrichment of genes involved in neuronal development ( MEIS2, FEV ) [75,78–80] and serotonin catalysis and reuptake ( TPH1, SLC6A4 ) [75,79,80,83]. Together these findings suggest that delta and PP/gamma cells act as the “brains” of the pancreatic islets, capable of receiving and integrating various neuronal signals to coordinate islet function.…”
Pancreatic islet dysfunction and beta cell failure are hallmarks of type 2 diabetes (T2D) pathogenesis. In this review, we discuss how genome-wide association studies (GWASs) and recent developments in islet (epi)genome and transcriptome profiling (particularly single cell analyses) are providing novel insights into the genetic, environmental, and cellular contributions to islet (dys)function and T2D pathogenesis. Moving forward, study designs that interrogate and model genetic variation (e.g., allelic profiling and (epi)genome editing) will be critical to dissect the molecular genetics of T2D pathogenesis, to build next-generation cellular and animal models, and to develop precision medicine approaches to detect, treat, and prevent islet (dys)function and T2D.
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