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Items: 10
1.
Ye L, Robertson MA, Hesselson D, Stainier DY, Anderson RM.
Development. 2015 Apr 15;142(8):1407-17. doi: 10.1242/dev.117911.
The interconversion
of cell lineages via transdifferentiation is an adaptive mode of tissue
regeneration and an appealing therapeutic target. However, its clinical
exploitation is contingent upon the discovery of contextual regulators
of cell fate acquisition and maintenance. In murine models of diabetes,
glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet.
However, the molecular triggers of this mode of regeneration are
unknown. Here, using lineage-tracing assays in a transgenic zebrafish
model of beta cell ablation, we demonstrate conserved plasticity of
alpha cells during islet
regeneration. In addition, we show that glucagon expression is
upregulated after injury. Through gene knockdown and rescue approaches,
we also find that peptides derived from the glucagon gene are necessary
for alpha-to-beta cell fate switching. Importantly, whereas beta cell
neogenesis was stimulated by glucose, alpha-to-beta cell conversion was
not, suggesting that transdifferentiation is not mediated by
glucagon/GLP-1 control of hepatic glucose production. Overall, this
study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells.
It further reveals that glucagon plays an important role in maintaining
endocrine cell homeostasis through feedback mechanisms that govern cell
fate stability.
© 2015. Published by The Company of Biologists Ltd.
© 2015. Published by The Company of Biologists Ltd.
KEYWORDS:
Alpha cell; Arx; Arxa; Beta cell; GLP-1; Gcga; Glucagon; Insulin; Pancreas; Pancreatic progenitor; Regeneration; Transdifferentiation; Zebrafish
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2.
Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL.
Nature. 2014 Oct 23;514(7523):503-7. doi: 10.1038/nature13633. Epub 2014 Aug 20.
Total or near-total loss of insulin-producing β-cells
occurs in type 1 diabetes. Restoration of insulin production in type 1
diabetes is thus a major medical challenge. We previously observed in
mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells
begin producing insulin by a process of reprogramming
(transdifferentiation) without proliferation.
Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
Comment in
- Diabetes: reprogrammed pancreatic δ-cells restore insulin production. [Nat Rev Endocrinol. 2014]
- PMID:
- 25141178
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC4209186
Kommenttini:
Mahdollisesti ihmiskunnassa on toimimassa tällaiset interkonversiot ammoisista ajoista, jota ei ole huomattu ja vasta kun sen resurssit on käytetty loppuun on merkkejä kliinisestä homeostaasin häiriöstä.jota sanotaan diabetesepidemiaksi.
Jos tätä interkonversiota fysiologisesti ilmenee, pitäisi löytää varhaiset merkitsijät, jotta voitaisiin asettaa varhaispreventiiviset dieetit ja muut suojaavat elintapatekijät ajoissa. Mahdollisesti tuo interkonversio on normaliteetti yhteiskunnassa, ja joutuu vasta hyvinvointivaltioissa liian suureen rasitukseen. tai maissa, jossa on energian ylisuuri puute tai perusravinnossa toksista energiaa. Siis itseasiassa käsittää koko ihmiskunnan glukoositasapainon trapetsilla elintapojensa takia.
3.
Kopinke D, Brailsford M, Pan FC, Magnuson MA, Wright CV, Murtaugh LC.
Dev Biol. 2012 Feb 1;362(1):57-64. doi: 10.1016/j.ydbio.2011.11.010. Epub 2011 Nov 29.
- PMID:
- 22146645
4.
Gannon M, Ables ET, Crawford L, Lowe D, Offield MF, Magnuson MA, Wright CV.
Dev Biol. 2008 Feb 15;314(2):406-17. Epub 2007 Nov 4.
- PMID:
- 18155690
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