Pancreatic β-cells are generated by neogenesis from non-β-cells after birth

Nakamura, Kenya; Minami, Kohtaro; Tamura, K.; Iemoto, Keisuke; Miki, Takashi; Seino, Susumu

doi:10.2220/biomedres.32.167

Cited by 26 publications

(27 citation statements)

References 36 publications

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“…These levels of Ngn3 mRNA in β cells (green and yellow cells) are higher than might be expected for cells in an adult pancreas, but are consistent with reports of NGN3 immunostaining in adult β cells (25,(33)(34)(35). Our findings of the absence of yellow cells in the pancreas after P5 suggest that β cell neogenesis does not occur after the early postnatal period (36).…”

Section: Introductionsupporting

confidence: 91%

No evidence for β cell neogenesis in murine adult pancreas

Xiao¹,

Chen²,

Shiota³

et al. 2013

J. Clin. Invest.

184

238

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Whether facultative β cell progenitors exist in the adult pancreas is a major unsolved question. To date, lineage-tracing studies have provided conflicting results. To track β cell neogenesis in vivo, we generated transgenic mice that transiently coexpress mTomato and GFP in a time-sensitive, nonconditional Cre-mediated manner, so that insulin-producing cells express GFP under control of the insulin promoter, while all other cells express mTomato (INS Cre mTmG mice). Newly differentiated β cells were detected by flow cytometry and fluorescence microscopy, taking advantage of their transient coexpression of GFP and mTomato fluorescent proteins. We found that β cell neogenesis predominantly occurs during embryogenesis, decreases dramatically shortly after birth, and is completely absent in adults across various models of β cell loss, β cell growth and regeneration, and inflammation. Moreover, we demonstrated upregulation of neurogenin 3 (NGN3) in both proliferating ducts and preexisting β cells in the ligated pancreatic tail after pancreatic ductal ligation. These results are consistent with some recent reports, but argue against the widely held belief that NGN3 marks cells undergoing endocrine neogenesis in the pancreas. Our data suggest that β cell neogenesis in the adult pancreas occurs rarely, if ever, under either normal or pathological conditions.

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Section: Introductionsupporting

confidence: 91%

No evidence for β cell neogenesis in murine adult pancreas

Xiao¹,

Chen²,

Shiota³

et al. 2013

J. Clin. Invest.

184

238

View full text Add to dashboard Cite

show abstract

“…alpha or delta cells) and mesenchymal stromal cells from bone marrow have been identified as beta cell precursors [30]. In contrast, lineage-tracing studies in mice show that only the beta cell itself serves as a beta cell source through self-duplication [31], although this was recently not confirmed [32] and is challenged by the fact that alpha cells [33,34], acinar cells [35,36] and ductal cells [37] are also sources for new beta cell formation, the last of which has been confirmed in the current study. Another source of beta cells is facultative progenitors in regenerating pancreatic ducts [30].…”

Section: Discussionmentioning

confidence: 99%

TCF7L2 promotes beta cell regeneration in human and mouse pancreas

et al. 2012

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Aims/hypothesis Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. Methods Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. Results TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/ STAT3 pathway. Conclusions/interpretation The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.

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“…Additionally, the negative result in Dor et al may be caused by their failure to examine the neonatal period or the new lobes after pancreatectomy (see below). Using the same approach, Nakamura et al recently examined the neonatal period and reported that neogenesis occurred in the second to third week after birth, but not in adults [21].…”

Section: Abbreviationsmentioning

confidence: 99%

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Bonner-Weir

Guo

Li³

et al. 2012

Rev Diabet Stud

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■ AbstractDiabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

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Pancreatic β-cells are generated by neogenesis from non-β-cells after birth

Cited by 26 publications

References 36 publications

No evidence for β cell neogenesis in murine adult pancreas

No evidence for β cell neogenesis in murine adult pancreas

TCF7L2 promotes beta cell regeneration in human and mouse pancreas

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

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