First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass

Wang, Guangliang; Rajpurohit, Surendra Kumar; Delaspre, Fabien; Walker, Steven L.; White, David T.; Ceasrine, Alexis M; Kuruvilla, Rejji; Li, Ruo‐Jing; Shim, Joong Sup; Liu, Jun O.; Parsons, Michael; Mumm, Jeff S.

doi:10.7554/elife.08261

Cited by 85 publications

(80 citation statements)

References 70 publications

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“…In the zebrafish, a population of pancreatic Notch-responsive cells have been well recognized for their progenitor capacity during development (Dalgin and Prince, 2015; Delaspre et al, 2015; Delous et al, 2012; Huang et al, 2014; Manfroid et al, 2012; Ninov et al, 2012; Parsons et al, 2009; Rovira et al, 2011; Wang et al, 2015; Wang et al, 2011). Recently, these cells have been revealed to be specialized ductal cells called centroacinar cells (CACs) (Delaspre et al, 2015), which also serve as progenitors to regenerate β cells in the adult zebrafish (Delaspre et al, 2015; Ghaye et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Centroacinar cells: At the center of pancreas regeneration

Beer

Parsons

Rovira

2016

Developmental Biology

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The process of regeneration serves to heal injury by replacing missing cells. Understanding regeneration can help us replace cell populations lost during disease, such as the insulin-producing β cells lost in diabetic patients. Centroacinar cells (CACs) are a specialized ductal pancreatic cell type that act as progenitors to replace β cells in the zebrafish. However, whether CACs contribute to β-cell regeneration in adult mammals remains controversial. Here we review the current understanding of the role of CACs as endocrine progenitors during regeneration in zebrafish and mammals.

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Section: Introductionmentioning

confidence: 99%

Centroacinar cells: At the center of pancreas regeneration

Beer

Parsons

Rovira

2016

Developmental Biology

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“…The kinetics of rod cell regeneration was assessed using fluorescent plate reader-based quantification (i.e., automated reporter quantification in vivo, ARQiv) of YFP signal levels in individual larvae (20,51,52). Using this method, we had previously shown full regeneration of rod cells as early as day 5-6 of recovery (20).…”

Section: Microglia/macrophages Are Necessary For Normal Rod Photorecementioning

confidence: 99%

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

159

218

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Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions. retina | microglia | glucocorticoid | regeneration | macrophage N eurodegenerative diseases are caused by the loss of discrete neuronal cell types. The goal of regenerative medicine is to reverse this process. One strategy for doing so involves harnessing the regenerative potential of endogenous neural stem cells. Unfortunately, although adult neural stem cells exist in the mammalian CNS, innate potentials for neuronal repair remain dormant in the absence of exogenous stimulation. Conversely, many other species are endowed with remarkable capacities for neuronal regeneration. For instance, in the zebrafish eye, retinal Müller glia (MG) cells can dedifferentiate to a stem cell-like state and give rise to progenitors that replace lost neurons and restore visual function (1, 2). Intriguingly, human MG cells are able to give rise to new neurons in culture (3) that can restore visual function when transplanted into mammalian disease models (4), suggesting that human MG retain a stem cell-like capacity for mediating retinal repair. Mechanisms controlling the regenerative potential of MG are therefore of great interest. We and others study zebrafish to learn more about how retinal regeneration is cont...

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“…Recently, a quantitative wholeorganism screening method combining high-throughput screening instrumentation with reporter-based assays was developed to identify compounds that elevated insulin reporter activity. 94 Over 500 000 zebrafish embryos were screened and 177 drugs implicated as candidates to treat β-cell paucity in diabetic patients. Importantly, a proportion of these candidates were already approved for use in humans highlighting the plausibility of rapid clinical translation of such screening approaches.…”

Section: Small-molecule Drugsmentioning

confidence: 99%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

153

162

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Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.

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First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass

Cited by 85 publications

References 70 publications

Centroacinar cells: At the center of pancreas regeneration

Centroacinar cells: At the center of pancreas regeneration

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

The zebrafish eye—a paradigm for investigating human ocular genetics

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