Beta-cell ontogeny: growth and death.

Abstract

Our understanding of the birth and death of the pan-creatic beta cell is of obvious importance to the cureof diabetes mellitus: whether to expand tissue fortransplantation, to bioengineer new cells or to induceislet regeneration in vivo. The scientific interest inthis questionhas risen in recent years, and this sessionfocuses on some of the important issues.Co-Chair Susan Bonner-Weir briefly introducedthe topic of beta-cell growth. For many years betacells were considered to be terminally differentiatedand unchanging after birth. However based on ex-perimental animal models the concept that the massof beta cells is not static but dynamic with the abilityto compensate (increase or decrease) in an effort tomaintain glucose homeostasis has been proposed [1].In contrast to the massive destruction of the beta cellsresulting in insulin-dependent diabetes mellitus(IDDM), a normal slow turnover of beta cells isachieved by the careful balance of beta-cell birthand beta-cell death by apoptosis. It is important to re-member that cell birth has two components: 1) differ-entiation from undifferentiated precursor cells (neo-genesis) as in embryonic development or as can be in-duced in the adult, and 2) replication of the differen-tiated beta cell. The excitement in this field is thatthe molecular control of these processes is beginningto unfold; this excitement is reflected in this session.The presentationsand discussionon beta-cell birthand death focused on transcription factors, externalcues such as mesenchymal interactions, matrix ele-ments, cytokines and growth factors. These topicsoverflowed to other sessions (German, Hayek, New-gard, Efrat). The underlying questions addressed in-cluded:1. What directs differentiation of beta cells from theundifferentiated precursor cells?2. What allows the maintenance of a differentiatedphenotype for beta cells?3. Can we ultimately make new beta cells from pre-cursor cells? from pre-existing beta cells or evenfrom unrelated, non-pancreatic cells?4. Are there reasons that beta cells are more suscepti-ble to injury/death than most other cells?As a start Dr. Bonner-Weir noted some of the pastadvances in this field. While a number of exciting pa-pers were written on pancreatic morphogenesis in the1960s and 1970s, the chapter by Pictet and Rutter in1972 [2] is generally considered the seminal paper inthis field. In the mid 1980s and early 1990s regenera-tion, growth and expansion of the beta cells in adultrodents in vivo by neogenesis and/or enhanced repli-cation had been reported after partial pancreatect-omy, ductal ligation, cellophane wrapping and over-expression of growth factors/cytokines in transgenicmice. In 1988 two groups showed a transient co-loca-lization of glucagon and insulin during embryonic de-velopment of rodent pancreas. These papers were thefirst of many presenting a schema of cell lineage forthe endocrine pancreas. Even though there is nowagreement that peptide YY is the first islet hormoneexpressed and that islet cells go through a transitionalstage of expressing more than one hormone, thequestion of lineage and markers of it is still not re-solved. In 1991 Dudek and co-authors [3] showedislet neoformation from transplanted adult rat ductsstripped of their mesenchyme and wrapped in fetal