Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2016)

It is well recognized that the regenerative capacity of pancreatic insulin-producing beta cells declines with age, with the most dramatic reduction occurring shortly after birth. However, the mechanism that accounts for this decline remains poorly understood. We sought to determine the molecular changes that attribute to this decrease in beta cell proliferation. Here, we show that activation of the DNA damage response (DDR) coincides with the decline in beta cell proliferation occurring during early postnatal life. In addition, we discovered a postnatal increase in the expression levels of replication stress-related DNA damage markers such as replication protein A (RPA) and phosphorylated Chk1 (pChk1). Furthermore, inhibition of the downstream effector Wee1 increases beta cell proliferation in vitro and in vivo. The results of this study provide insight into age-dependent changes in beta cells that lead to the increased incidence of cell cycle arrest. We hope that these findings will not only contribute to uncovering mechanisms underlying the age-dependent decline in beta cell proliferation, but also assist in the identification of factors that could potentially be pharmacologically targeted to improve beta cell function and stimulate their expansion for the management and treatment of diabetes mellitus.

    Cover page: DNA damage-induced replication stress mediates cell cycle arrest in postnatal pancreatic beta cells
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2017)
    Pancreatic β cell mass for appropriate blood glucose control is established during early postnatal life. β cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of β cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of β cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This analysis captured signatures of immature, proliferative β cells and established high expression of amino acid metabolic, mitochondrial, and Srf/Jun/Fos transcription factor genes as their hallmark feature. Experimental validation revealed high metabolic activity in immature β cells and a role for reactive oxygen species and Srf/Jun/Fos transcription factors in driving postnatal β cell proliferation and mass expansion. Our work provides the first high-resolution molecular characterization of state changes in postnatal β cells and paves the way for the identification of novel therapeutic targets to stimulate β cell regeneration.
      Cover page: Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation
      Top