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Age-related Islet Inflammation Marks the Proliferative Decline of Pancreatic Beta-cells in Zebrafish

ABSTRACT: Age-related Islet Inflammation Marks the Proliferative Decline of Pancreatic Beta-cells in Zebrafish

PROVIDER: PRJNA418467 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6293903_1.fastq.gz	Fastqsanger.gz
	SRR6293903_2.fastq.gz	Fastqsanger.gz
	SRR6293904_1.fastq.gz	Fastqsanger.gz
	SRR6293904_2.fastq.gz	Fastqsanger.gz
	SRR6293905_1.fastq.gz	Fastqsanger.gz

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Project description:Individual organisms age at different rates, however, it remains unclear how aging alters the properties of individual cells. Here we show that zebrafish pancreatic beta-cells exhibit heterogeneity in both gene expression and proliferation with age. Individual beta-cells show marked variability in transcripts involved in endoplasmic reticulum stress, inhibition of growth factor signaling and inflammation, including NF-kB signaling. Using a reporter line, we show that NF-kB signaling is indeed activated heterogeneously with age. Notably, beta-cells with higher NF-kB activity proliferate less compared to neighbors with lower activity. Furthermore, NF-kB-signalinghigh beta-cells from younger islets upregulate socs2, a gene naturally expressed in beta-cells from older islets. In turn, socs2 can inhibit proliferation cell-autonomously. NF-kB activation correlates with the recruitment of tnfα-expressing immune cells, pointing towards a role for the islet microenvironment in this activity. We propose that aging is heterogeneous across individual beta-cells and identify NF-kB signaling as a marker of heterogeneity.

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Project description:The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnf?-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta-cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signalinghi cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age.

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Identification of proliferative and mature Î²-cells in the islet of Langerhans

Project description:Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of Î²-cells. Pancreatic Î²-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential1-5, thus understanding the mechanisms underlying this functional heterogeneity might allow novel regenerative approaches. Here we discovered Flattop (Fltp) as a biomarker that distinguishes proliferative from mature Î²-cells. Genetic lineage tracing revealed that these Î²-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- Î²-cells undergo compensatory proliferation, whereas Fltp-lineage+ Î²-cells account for islet cell hypertrophy commonly associated with cytotoxic stress. The expression of the Wnt/planar cell polarity (PCP) effector gene Fltp increases when naÃ¯ve Î²-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs6-8. We show that dispersed early postnatal islet cells, insulinoma cells and human Î²-cells all have the intrinsic ability to form polarized pseudo-islets in 3D cultures. Compaction and polarization correlates with the induction of maturation markers and can be enhanced by Wnt/PCP pathway activation. Finally, we show that Fltp is not only a marker for mature Î²-cells, but is also functionally required for proper insulin secretion in mouse and human. We conclude that planar cell polarity and 3D architecture underlie functional Î²-cell heterogeneity and report that Fltp is a biomarker that separates proliferative from mature Î²-cells. These findings establish novel molecular underpinnings of Î²-cells and enable targeting of subpopulations for the regeneration of functional Î²-cell mass in diabetic patients. We performed gene expression microarray analysis on two FACS-sorted pancreatic islet cell populations: flattop-positive and flattop-negative.

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Project description:Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential, thus understanding the mechanisms underlying this functional heterogeneity might allow novel regenerative approaches. Here we discovered Flattop (Fltp) as a biomarker that distinguishes proliferative from mature β-cell subpopulations with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that these β-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- β-cells undergo compensatory proliferation, whereas Fltp-lineage+ β-cells account for islet cell hypertrophy commonly associated with cytotoxic stress. The expression of the Wnt/planar cell polarity (PCP) effector gene Fltp increases when naïve β-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger mouse and human β-cell maturation. Finally, we show that Fltp is not necessary for β-cell development, proliferation, or maturation, but is required for proper glucose-stimulated insulin secretion in mature β-cells. We conclude that 3D architecture and Wnt/PCP signaling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a biomarker for mature β-cells establish novel molecular underpinnings of β-cells and enable targeting of subpopulations for the regeneration of functional β-cell mass in diabetic patients.

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