Beta cell progenitors in adult pancreas

Project Details

Description

Rationale Diabetes patients have a shortage in beta cells and insulin and consequently develop an increased risk of chronic periods of hyperglycemia, causing serious secondary complications. Transplantation of donor beta cells provides a solution but a shortage of human donor organs prevents its general application (Pipeleers et al, 2002). Therefore alternative cell sources and strategies for beta cell regeneration are needed. We recently discovered that under conditions of severe injury progenitors contribute to the formation of new adult beta cells. These adult beta cell progenitors were identified, characterized and isolated by tracing cells that expressed neurogenin 3 (Ngn3), a marker for embryonic beta cell progenitors. The adult Ngn3+ cells could be differentiated to beta cells. The Ngn3+ cells, however, did not proliferate and thus present a limited cell pool. We therefore aim to identify and isolate the progenitors of the Ngn3+ cells, the Pdx1+ cells because on the basis of their embryonic characteristics these are expected to be an expandable pool that thus could give rise to increased beta cell numbers. In addition we wish to identify the factors that are responsible for the activation of the early, pre-Ngn3+, progenitors of beta cells. Focus will be on the role of macrophages in beta cell regeneration because they are a central part of innate immunity and accumulating recent evidence from a number of fields points to the essential roles played by macrophages in tissue dynamics, and specifically in organ regeneration and remodeling (Schwartz et al., 2006; Duffield et al., 2005; Grunewald et al., 2006). Specific Aims SA1. Identification, isolation & characterization of adult, undifferentiated Pdx1+ cells. SA2. Expansion and differentiation of the isolated adult, undifferentiated Pdx1+ cells. SA3. Identification of the signals that activate beta cell progenitors: the role of macrophages. Background and Significance of this work Achievements by others. Numerous mechanisms that control differentiation of endocrine progenitor cells in the embryonic pancreas have been disclosed (Jensen, 2004) but our knowledge on the existence of precursors and generation of islet cells in the postnatal pancreas depends merely on descriptive data and indirect proof (Bonner-Weir and Weir, 2005; Bouwens and Rooman, 2005). Long-term culture of heterogeneous populations of pancreas cells favors enrichment of beta celllike phenotypes (Bonner-Weir et al., 2000; Seaberg et al., 2004; Suzuki et al., 2004) that under certain conditions were able to reverse hyperglycemia when transplanted in diabetic mice (Hao et al., 2006; Ramiya et al., 2000). None of these studies, however, was conclusive in demonstrating the existence and origin of a bona fide beta cell progenitor in postnatal pancreas. The elusiveness of this cell type reached a summit when genetic lineage tracing provided evidence that pre-existing beta cells, rather than stem/progenitor cells, are the major source of new beta cells in adult mice both under normal physiological conditions and after 70% or 50% pancreatectomy (Dor et al., 2004; Teta et al., 2007). Our own achievements. Two major problems are at the basis of the ambiguity about the origin of beta cell neogenesis: the slow turnover of adult beta cells and the lack of specific markers to trace their origin. We overcame these hurdles by (i) forcing the generation of new beta cells through partial duct ligation (PDL) in the pancreas of adult mice and (ii) using transgenic reporter mice that allow tracing of the promoter activity of Ngn3 as a marker of adult progenitor cell recruitment. PDL stimulates doubling of the beta cell mass in rats (Wang et al., 1995). Ngn3 is an essential master switch for differentiation of embryonic islet cell progenitors (Apelqvist et al., 1999; Gradwohl et al., 2000; Gu et al., 2002; Schwitzgebel et al., 2000) and transdifferentiation of adult and neonatal cells of the exocrine pancreas towards beta cells (Baeyens et al., 2006; Harb et al., 2006; Heremans et 2/29/08, 11:42 AM Onderzoeksproject FWO, Harry Heimberg 2/12 al., 2002; Rescan et al., 2005) and are extremely rare in normal post-natal pancreas (Gu et al., 2002). We thus showed that partial duct ligation caused an inflammatory response limited to the injured part of the pancreas and that under these conditions beta cell progenitors can be activated in adult mouse pancreas. Differentiation of the adult progenitors is Ngn3-dependent and gives rise to all islet cell types, including glucose responsive beta cells. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional beta cell mass by differentiation and proliferation rather than by self-duplication of pre-existing beta cells only (Xu et al., 2008). The molecular mechanisms mediating this process are not clear, but are thought to result from the wealth of cytokines released by macrophages in the proximity of the damaged tissue. These cytokines may act either on local vasculature, local parenchymal cells or both. Thus, our hypothesis is that macrophages are important regulators, either direct or indirect, of pancreatic beta cell regeneration. The implication of this hypothesis, if validated, is that manipulations of macrophage biology may provide novel means for the enhancement of beta cell regeneration.
AcronymFWOAL510
StatusFinished
Effective start/end date1/01/0931/12/12

Keywords

  • Cell Therapy
  • Prevention
  • Transplantation
  • Diagnostic Tests
  • Immunology
  • Cell Death and Survival
  • Islet Cell Pathology
  • Islet Cell Biology
  • Beta Cell Transplantation
  • Diabetes

Flemish discipline codes

  • Basic sciences
  • Biological sciences