Investigating pancreatic beta cell production and function

 

The vertebrate pancreas includes exocrine and endocrine tissues that are responsible for digesting food and regulating sugar metabolism, respectively. Several diseases associate with the pancreas, including pancreatitis, diabetes, and pancreatic cancer, amongst which diabetes is the most prevalent that inflicts more than 27 million individuals in the United States.  

 

We investigate the cellular and molecular mechanisms underlying islet cell differentiation and function, which include multiple endocrine cell types that secrete insulin (beta cells), glucagon (alpha cells), somatostatin (delta cells), and pancreatic polypeptide (PP cells), respectively. Our basic strategy is to first unambiguously identify progenitors of each specific cell type, then examine the molecular networks and cellular interactions for their development and function. Our studies focus on the following areas:

 

1)   Technology development: A challenge of studying development and organogenesis in mammals is our inability to follow specific cells during their development to understand thwir specification and function. The Cre-Lox-based technology allows for temporal and spatial cell marking and gene activity manipulation, with a drawback of marking all cells that express Cre that includes multiple cell types. We have engineered two inactive Cre fragments that can reconstitute Cre in cells that simultaneously express dual protein markers. This enabled the identification of beta-cell progenitor cells and high-resolution analysis of the genetic/epigenetic programs that direct the production of functional beta cells. It also allows us to examine how seemingly identical progenitor cells adopt different cell fate, either as pre-deterministic or stochastic model. In the former possibility, progenitor may have differential gene expression and differentiation potentials. In the later model, progenitor cells are identical, yet stochastic transcription of certain factors could bias progenitors to specific cell fate.

2)   Novel mode of cell-cell communication for coordinated cellular differentiation: Notch-mediated cell-cell interactions were known to select a specific set of pancreatic cells as endocrine progenitors by activating the expression of Ngn3. Yet Notch signaling alone cannot account for the coordinated differentiation of neighboring cells adopt islet cell fate at same time windows. We have shown that gap junction-mediated information can control this coordinated differentiation. We are currently exploring whether miRNA-based mechanism coordinate endocrine cell differentiation through gap junctions, aided by RNASeq- and miRNAseq-based techniques.

3)   Differentiation, survival, and function. With state-of-the-art technologies such as FACS-based cell sorting, RNAseq, and CHIPseq, we purify intermediate cell populations that have defined function and examine the genetic networks that direct cell differentiation and function. These studies avoid complications caused by unwanted cell types in tissue samples. We have identified several previously unidentified gene circuits that might participate endocrine differentiation and their role in islet production are being examined. We also identify factors that maintain beta cell survival during their function and stress, such as the Myt1 family of transcription factors. Lastly, we investigate how cellular structures, such as microtubules, direct beta cell function, in insulin vesicular transport and secretion. We are currently working on a hypothesis that microtubules in pancreatic beta cells act as a storage structure to fine-tune insulin secretion.

 

Publications

Featured publications

  1. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H (2014) Nat Biotechnol 32(1): 76-83
    › Primary publication · 24240391 (PubMed) · PMC4096987 (PubMed Central)
  2. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Sugiyama T, Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK (2013) Proc Natl Acad Sci U S A 110(31): 12691-6
    › Primary publication · 23852729 (PubMed) · PMC3732989 (PubMed Central)
  3. Generation of islet-like cells from mouse gall bladder by direct ex vivo reprogramming. Hickey RD, Galivo F, Schug J, Brehm MA, Haft A, Wang Y, Benedetti E, Gu G, Magnuson MA, Shultz LD, Lagasse E, Greiner DL, Kaestner KH, Grompe M (2013) Stem Cell Res 11(1): 503-15
    › Primary publication · 23562832 (PubMed) · PMC3940065 (PubMed Central)
  4. Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. Liu J, Willet SG, Bankaitis ED, Xu Y, Wright CV, Gu G (2013) Genesis 51(6): 436-42
    › Primary publication · 23441020 (PubMed) · PMC3696028 (PubMed Central)
  5. Modulation of Golgi-associated microtubule nucleation throughout the cell cycle. Maia AR, Zhu X, Miller P, Gu G, Maiato H, Kaverina I (2013) Cytoskeleton (Hoboken) 70(1): 32-43
    › Primary publication · 23027431 (PubMed) · PMC3574797 (PubMed Central)
  6. Ngn3(+) endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium. Magenheim J, Klein AM, Stanger BZ, Ashery-Padan R, Sosa-Pineda B, Gu G, Dor Y (2011) Dev Biol 359(1): 26-36
    › Primary publication · 21888903 (PubMed) · PMC3746519 (PubMed Central)
  7. Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. Ray KC, Bell KM, Yan J, Gu G, Chung CH, Washington MK, Means AL (2011) PLoS One 6(2): e16786
    › Primary publication · 21311774 (PubMed) · PMC3032792 (PubMed Central)
  8. Gαo represses insulin secretion by reducing vesicular docking in pancreatic beta-cells. Zhao A, Ohara-Imaizumi M, Brissova M, Benninger RK, Xu Y, Hao Y, Abramowitz J, Boulay G, Powers AC, Piston D, Jiang M, Nagamatsu S, Birnbaumer L, Gu G (2010) Diabetes 59(10): 2522-9
    › Primary publication · 20622165 (PubMed) · PMC3279551 (PubMed Central)
  9. Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas. Wang S, Yan J, Anderson DA, Xu Y, Kanal MC, Cao Z, Wright CV, Gu G (2010) Dev Biol 339(1): 26-37
    › Primary publication · 20025861 (PubMed) · PMC2824035 (PubMed Central)
  10. Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Wang S, Jensen JN, Seymour PA, Hsu W, Dor Y, Sander M, Magnuson MA, Serup P, Gu G (2009) Proc Natl Acad Sci U S A 106(24): 9715-20
    › Primary publication · 19487660 (PubMed) · PMC2701002 (PubMed Central)

Community Leaders

  • Guoqiang Gu
    Assistant Professor of Cell and Developmental Biol

Contact Information

2213 Garland Avenue
9415 MRB IV
Nashville, TN 37232
USA
615-936-3632 (p)

Guoqiang Gu
615-936-3634 (p)
Email

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

Animals beta cells Blotting, Western Cell Cycle cell death cell differentiation cell division cell function cell lineage cell maintenance cell marking Electroporation Embryonic and Fetal Development Endocrine System Endothelial Cells Epidermal Growth Factor Glycine GTP-Binding Protein alpha Subunits Intestine, Small islets Islets of Langerhans Keratin-19 Leucine Zippers Mitosis Mutation, Missense Pancreatic Ducts pancreatic progenitors Pregnancy regeneration Stem Cells Touch