Alpha Cells Beget Beta Cells
2009; Cell Press; Volume: 138; Issue: 3 Linguagem: Inglês
10.1016/j.cell.2009.07.022
ISSN1097-4172
Autores Tópico(s)Diabetes and associated disorders
ResumoUnderstanding the origins of insulin-producing beta cells of the pancreas could lead to new treatments for diabetes. Collombat et al., 2009Collombat P. Xu X. Ravassard P. Sosa-Pineda B. Dussaud S. Billestrup N. Madsen O.D. Serup P. Heimberg H. Mansouri A. Cell. 2009; (this issue)PubMed Google Scholar now show that in response to injury, a population of pancreatic progenitor cells can give rise to glucagon-expressing alpha cells that then transdifferentiate into beta cells. Understanding the origins of insulin-producing beta cells of the pancreas could lead to new treatments for diabetes. Collombat et al., 2009Collombat P. Xu X. Ravassard P. Sosa-Pineda B. Dussaud S. Billestrup N. Madsen O.D. Serup P. Heimberg H. Mansouri A. Cell. 2009; (this issue)PubMed Google Scholar now show that in response to injury, a population of pancreatic progenitor cells can give rise to glucagon-expressing alpha cells that then transdifferentiate into beta cells. Diabetes results from loss of the insulin-producing beta cells of the pancreatic islets. A clear identification of the progenitor cell population that gives rise to beta cells and an understanding of the factors and the cellular mechanisms that govern beta cell regeneration may lead to new and more effective treatments for diabetes. The paired homeobox transcription factor Pax4 has been implicated in the control of endocrine cell fate during pancreas development. Mice lacking Pax4 have diminished numbers of beta cells and instead accumulate alpha cells, a cell type that expresses the hormone glucagon (Sosa-Pineda et al., 1997Sosa-Pineda B. Chowdhury K. Torres M. Oliver G. Gruss P. Nature. 1997; 386: 399-402Crossref PubMed Scopus (634) Google Scholar). In this issue, Collombat et al., 2009Collombat P. Xu X. Ravassard P. Sosa-Pineda B. Dussaud S. Billestrup N. Madsen O.D. Serup P. Heimberg H. Mansouri A. Cell. 2009; (this issue)PubMed Google Scholar demonstrate that the alpha cell lineage is endowed with an unusual plasticity after tissue injury: when Pax4 is ectopically expressed in the alpha cells of mice at a dose equivalent to its physiological level, it instructs these cells to become functional beta cells (Figure 1). The major function of alpha cells is to produce the hormone glucagon, which, in counter-regulation to the actions of insulin, stimulates hepatic glucose production to maintain blood glucose levels during fasting (Gromada et al., 2007Gromada J. Franklin I. Wollheim C.B. Endocr. Rev. 2007; 28: 84-116Crossref PubMed Scopus (432) Google Scholar). In prior work, it has been shown that glucagon-expressing cells are the earliest identifiable cells of the endocrine lineage during pancreas development, suggesting that glucagon-expressing cells may be endocrine progenitor cells (Gromada et al., 2007Gromada J. Franklin I. Wollheim C.B. Endocr. Rev. 2007; 28: 84-116Crossref PubMed Scopus (432) Google Scholar). The study by Collombat et al. now provides unequivocal evidence for progenitor cells that exist in the tissue surrounding the duct linings of pancreas. These progenitor cells express the transcription factor neurogenin 3 (Ngn3), proliferate, and adopt an alpha cell identity. They then rapidly transdifferentiate into insulin-secreting beta cells. The rapid transition from alpha cell to beta cell results in a relative deficiency of alpha cells and a subsequent loss of glucagon signaling. The loss of glucagon signaling stimulates the expression of Ngn3 in the progenitor cells associated with the duct and promotes their amplification. The increase in Ngn3 expression in progenitor cells appears to be a response to the increased expression of Pax4 in alpha cells and to the rapid depletion of alpha cells by their transition to beta cells. Evidence for this comes from the administration of exogenous glucagon to the Pax4 transgenic mice, which suppresses the proliferation of Ngn3-positive cells and their subsequent transition to alpha and then beta cells. Conversely, mice lacking the glucagon receptor (Vuguin et al., 2006Vuguin P.M. Kedees M.H. Cui L. Guz Y. Gelling R.W. Nejathaim M. Charron M.J. Teitelman G. Endocrinology. 2006; 147: 3995-4006Crossref PubMed Scopus (83) Google Scholar) display enhanced production of alpha cells. By using interfering RNAs to specifically inhibit Ngn3 activation, Collombat et al. show that the formation of new beta cells in response to the ectopic expression of Pax4 occurs via a molecular pathway that involves the activation of Ngn3, similar to the pathway that operates during embryonic development of the pancreas. A similar approach was used by Xu et al., 2008Xu X. D'Hoker J. Stangé G. Bonné S. De Leu N. Xiao X. Van de Casteele M. Mellitzer G. Ling Z. Pipeleers D. et al.Cell. 2008; 132: 197-207Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar in their seminal discovery of the critical role of Ngn3 in the specification of endocrine progenitor cells in the adult pancreas in response to injury. During embryogenesis, the glucagon gene (Gcg) is expressed in the earliest endocrine cells that can be detected. The findings of Collombat et al. challenge the previously held notion that mature insulin-producing cells do not derive from cells that originally express glucagon (Herrera, 2000Herrera P.L. Development. 2000; 127: 2317-2322Crossref PubMed Google Scholar). Collambat et al. use lineage-tracing experiments to assess islet regeneration in transgenic mice after administration of the toxin streptozotocin, which destroys beta cells. They show that the vast majority of newly formed beta cells originate from cells that previously expressed glucagon. This finding provides a convincing demonstration that alpha cells retain the potential to convert to beta cells in the adult pancreas. Moreover, the latent stem/progenitor cells adjacent to the ducts respond to alpha cell depletion by activating the formation and expansion of facultative endocrine progenitors. A decrease in the number of Ngn3-labeled cells and loss of beta cell hyperplasia occurs in Pax4-misexpressing mice treated with glucagon, underscoring the importance of glucagon in the feedback inhibition of alpha cell neogenesis. Interestingly, adaptive hyperplasia of endocrine cells often occurs by the sustained actions of trophic factors or a diminution of factors that suppress feedback inhibition. In pathophysiological conditions, such as sustained high glucose due to the development of insulin resistance in diabetes, beta cells exhibit hyperplasia in an attempt to produce more insulin to counteract hyperglycemia. Likewise, sustained hypoglycemia and hypoglucagonemia results in marked alpha cell hyperplasia. Of note, disruption of glucagon signaling, such as knockout of the glucagon receptor (Vuguin et al., 2006Vuguin P.M. Kedees M.H. Cui L. Guz Y. Gelling R.W. Nejathaim M. Charron M.J. Teitelman G. Endocrinology. 2006; 147: 3995-4006Crossref PubMed Scopus (83) Google Scholar) or deficiency of Pax4 (Sosa-Pineda et al., 1997Sosa-Pineda B. Chowdhury K. Torres M. Oliver G. Gruss P. Nature. 1997; 386: 399-402Crossref PubMed Scopus (634) Google Scholar), results in alpha cell hyperplasia. Paradoxically, alpha cell hyperplasia also occurs in conditions of insulin deficiency that result from injury of beta cells. For example, this occurs in mice (Li et al., 2000Li Z. Karlsson F.A. Sandler S. J. Endocrinol. 2000; 165: 93-99Crossref PubMed Scopus (83) Google Scholar) or monkeys (Dufrane et al., 2009Dufrane D. Maillart J.-F. Aouassar N. Goebbels R.-M. Guiot Y. Gianello P. Xenotransplantation. 2009; 16: 152-163Crossref PubMed Scopus (10) Google Scholar) given streptozotocin, or in NOD mice in which beta cells are injured by an autoimmune attack (Ogawa et al., 2004Ogawa N. List J.F. Habener J.F. Maki T. Diabetes. 2004; 53: 1700-1705Crossref PubMed Scopus (138) Google Scholar). In all of these models, the alpha cells appear to be blocked from, or incapable of, transformation into beta cells. The observations of Collombat et al. demonstrate that Pax4 alone is sufficient to overcome this block and raise the possibility that deficiency of glucagon or glucagon signaling may serve as a cue for the regeneration of both the alpha cells and duct-associated progenitor cells. In the transgenic mouse model studied by Collombat et al., the dramatic expansion of the beta cell mass throughout postnatal life is attributed to a continuous formation of beta cells through alpha cell reprogramming rather than the slow self-replication of pre-existing mature beta cells (Dor et al., 2004Dor Y. Brown J. Martinez O.I. Melton D.A. Nature. 2004; 429: 41-46Crossref PubMed Scopus (1816) Google Scholar). These observations provide proof that the adult pancreas has latent capabilities to regenerate new beta cells in response to injury and do so by resurrecting developmental programs to allow amplification of progenitor cells and selective lineage commitments. In this case, the beta cells originating from cells that express glucagon are fully functional and counter diabetes induced by streptozocin. This study will redirect thinking in the field of regenerative medicine in the treatment of diabetes, which has been focused on the premise that beta cell neogenesis only occurs through the replication of existing beta cells (Dor et al., 2004Dor Y. Brown J. Martinez O.I. Melton D.A. Nature. 2004; 429: 41-46Crossref PubMed Scopus (1816) Google Scholar). Finally, these studies show that replacement of endocrine tissue by transplantation of insulin-producing cells, derived from embryonic stem cells or other cells, is not the only feasible approach to a permanent treatment for diabetes. To the contrary, it is now possible to contemplate treatment approaches that coax pre-existing, latent stem/progenitor cells and alpha cells to make new beta cells. The Ectopic Expression of Pax4 in the Mouse Pancreas Converts Progenitor Cells into α and Subsequently β CellsCollombat et al.CellAugust 07, 2009In BriefWe have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature α cells, to adopt a β cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. Full-Text PDF Open Archive
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