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1 Molecular and Genetic Regulation of Pig Pancreatic Islet Cell Development 2 3 4 Seokho Kim1,9, Robert L

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1 Molecular and Genetic Regulation of Pig Pancreatic Islet Cell Development 2 3 4 Seokho Kim1,9, Robert L bioRxiv preprint doi: https://doi.org/10.1101/717090; this version posted January 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Molecular and genetic regulation of pig pancreatic islet cell development 2 3 4 Seokho Kim1,9, Robert L. Whitener1,9, Heshan Peiris1, Xueying Gu1, Charles A. Chang1, 5 Jonathan Y. Lam1, Joan Camunas-Soler2, Insung Park3, Romina J. Bevacqua1, Krissie Tellez1, 6 Stephen R. Quake2,4, Jonathan R. T. Lakey5, Rita Bottino6, Pablo J. Ross3, Seung K. Kim1,7,8 7 8 1Department of Developmental Biology, Stanford University School of Medicine, 9 Stanford, CA, 94305 USA 10 2Department of Bioengineering, Stanford University, Stanford, CA, 94305 USA 11 3Department of Animal Science, University of California Davis, Davis, CA, 95616 USA 12 4Chan Zuckerberg Biohub, San Francisco, CA 94518, USA. 13 5Department of Surgery, University of California at Irvine, Irvine, CA, 92868 USA 14 6Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, 15212 USA 15 7Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305 USA 16 8Stanford Diabetes Research Center, Stanford University School of Medicine, 17 Stanford, CA, 94305 USA 18 19 9These authors contributed equally 20 21 Correspondence and requests for materials should be addressed to S.K.K (email: 22 [email protected]) 23 24 Key Words: pancreas; metabolism; organogenesis; b-cell; a-cell; d-cell; diabetes mellitus 25 26 Summary Statement: This study reveals transcriptional, signaling and cellular programs 27 governing pig pancreatic islet development, including striking similarities to human islet 28 ontogeny, providing a novel resource for advancing human islet replacement strategies. 1 bioRxiv preprint doi: https://doi.org/10.1101/717090; this version posted January 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 29 Abstract 30 Reliance on rodents for understanding pancreatic genetics, development and islet function 31 could limit progress in developing interventions for human diseases like diabetes mellitus. 32 Similarities of pancreas morphology and function suggest that porcine and human pancreas 33 developmental biology may have useful homologies. However, little is known about pig 34 pancreas development. To fill this knowledge gap, we investigated fetal and neonatal pig 35 pancreas at multiple, crucial developmental stages using modern experimental approaches. 36 Purification of islet b-, a- and d-cells followed by transcriptome analysis (RNA-Seq) and 37 immunohistology identified cell- and stage-specific regulation, and revealed that pig and human 38 islet cells share characteristic features not observed in mice. Morphometric analysis also 39 revealed endocrine cell allocation and architectural similarities between pig and human islets. 40 Our analysis unveiled scores of signaling pathways linked to native islet b-cell functional 41 maturation, including evidence of fetal a-cell GLP-1 production and signaling to b-cells. Thus, 42 the findings and resources detailed here show how pig pancreatic islet studies complement 43 other systems for understanding the developmental programs that generate functional islet cells, 44 and that are relevant to human pancreatic diseases. 45 2 bioRxiv preprint doi: https://doi.org/10.1101/717090; this version posted January 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 46 Introduction 47 Progress from studies of pancreas biology in humans (Hart and Powers, 2019; Hrvatin et al., 48 2014b) has advanced our understanding of post-natal islet regulation and function. The 49 recognition that mouse pancreas biology – while essential – has limitations for understanding 50 human pancreas formation or diseases (Hattersley and Patel, 2017; Maestro et al., 2007), has 51 intensified interest in experimental systems that more closely reflect human pancreas 52 development (McKnight et al., 2010; Pan and Brissova, 2014). There is a specific, crucial 53 knowledge gap in our understanding of human islet and pancreas development from mid- 54 gestation through neonatal and juvenile stages, a period when critical aspects of islet 55 development are known to occur (Arda et al., 2016). The use of human primary tissues to 56 address such questions is limited by inter-individual heterogeneity, unpredictable and restricted 57 access to tissue from key developmental stages, and challenges implementing high-throughput 58 molecular approaches. Likewise, reconstitution of islet development from stem cell sources or 59 fetal human cell lines remains imperfect (Sneddon et al., 2018), thereby limiting interpretation of 60 developmental studies in those systems. 61 Humans and pigs are omnivorous mammals with similar physiology and metabolic diseases, 62 including diabetes mellitus and its complications, from diet-induced obesity, insulinopathy and b- 63 cell stress (Dyson et al., 2006; Lim et al., 2018; Renner et al., 2013). Recent experimental 64 advances expand possible studies of pig pancreas development to include gain- and loss-of- 65 function genetics (Kemter et al., 2017; Matsunari et al., 2013; Sheets et al., 2018; Wu et al., 66 2017), fetal surgery and immunomodulation (Fisher et al., 2013), and primary islet cell genetics 67 (Peiris et al., 2018). Prior studies of pig pancreas development have largely relied on 68 immunohistological survey of tissue cell types (Carlsson et al., 2010; Ferrer et al., 2008; 69 Hassouna et al., 2018; Nagaya et al., 2019). Moreover, studies linking hallmark islet functions, 70 like regulated insulin secretion and dynamic changes in gene expression at advancing 71 developmental stages, have not been previously reported (Mueller et al., 2013). Thus, pancreas 72 and metabolic research could benefit from systematic application of powerful methods like cell 73 purification by flow cytometry, high-throughput transcriptome analysis, and islet physiological 74 studies across a comprehensive range of pig developmental stages. 75 Here we apply these and other modern approaches to delineate pig pancreas development, 76 with a focus on islet b-cells, the sole source of insulin, and a-cells, the principal systemic source 77 of the hormone glucagon. Dysregulation of hormone secretion by these cells is thought to be a 78 leading cause of both type 1 diabetes (T1D) and type 2 diabetes (T2D) in humans (Holst et al., 79 2017; Lee et al., 2016). Our findings provide evidence of greater similarity between pig and 3 bioRxiv preprint doi: https://doi.org/10.1101/717090; this version posted January 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 80 human b-cells and a-cells than to cognate mouse cells, and demonstrate how studies of pig 81 pancreatic cells can advance our understanding of the genetic, molecular, signaling and 82 physiological programs that generate functional pancreatic islet cells. 83 84 Results 85 Pancreas dissociation and FACS purification of islet cells from fetal and neonatal pigs 86 To measure gene expression and functional changes in the developing pig pancreas, we 87 established a reliable infrastructure to procure pancreata from fetal or neonatal pigs using 88 rigorous criteria that optimized tissue quality and gene expression analysis (Fig. 1A). To 89 investigate the crucial period of ontogeny culminating in functional islet cells, we systematically 90 isolated pancreata from gestational days (d) 40, 70, 90 and post-natal days (P) 8 and 22 (Fig. 91 1A). We surveyed sorting methods based on cell surface epitopes, like in prior work with mouse 92 and human cells (Arda et al., 2016; Arda et al., 2018; Sugiyama et al., 2013), but have not yet 93 achieved reliable cell fractionation based with this strategy (R. Whitener and S. K. Kim, unpubl. 94 results). Instead, we used intracellular sorting with specific antibodies against insulin-, glucagon- 95 and somatostatin- to isolate b-, a- and d-cells, respectively, from fetal or neonatal pancreata 96 (Fig. S1A), like in prior work on human islets (Arda et al., 2016; Hrvatin et al., 2014a; Peiris et 97 al., 2018). Quantitative RT-PCR (qRT-PCR: Fig. 1B) confirmed enrichment or depletion of 98 expected marker genes for b- (INS), a- (GCG), d- (SST), ductal (KRT19) and acinar cells 99 (AMY2). 100 To obtain comprehensive gene expression profiles, we performed RNA-Seq on 37 libraries 101 generated from fetal and neonatal pancreatic cells (Table S1). An average of 7 million reads per 102 sample library uniquely mapped to a current pig reference transcriptome (Sscrofa11.1). 103 Unsupervised hierarchical clustering of transcriptome data with Pearson correlation analysis 104 revealed distinct expression profiles that changed with advancing developmental stage within 105 specific cell types (Fig. S1B). Principal component analysis with these samples showed that 106 transcriptomes clustered in the first principal component according to cell type (b-, a- or d-cells: 107 PC1, 35% of variance), and according to advancing developmental stage in the second principal 108 component (PC2, 25% of variance: Fig. S1C). Samples from ‘late fetal’ stages d70 and d90 109
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