In:
Endocrinology, The Endocrine Society, Vol. 150, No. 4 ( 2009-04-01), p. 1627-1635
Abstract:
The enigmatic process of β-cell maturation has significant implications for diabetes pathogenesis, and potential diabetes therapies. This study examined the dynamics and heterogeneity of insulin and pancreatic duodenal homeobox (Pdx)-1 gene expression in adult β-cells. Insulin and Pdx1 expression were monitored in human and mouse islet cells and MIN6 cells using a Pdx1-monomeric red fluorescent protein/insulin-enhanced green fluorescent protein dual-reporter lentivirus. The majority of fluorescent cells were highly positive for both Pdx1 and insulin. Cells expressing Pdx1 but little or no insulin (Pdx1+/Inslow) comprised 15–25% of the total population. Time-lapse imaging demonstrated that Pdx1+/Inslow primary β-cells and MIN6 cells could convert to Pdx1+/Ins+ cells without cell division. Genes involved in the mature β-cell phenotype (Glut2, MafA) were expressed at higher levels in Pdx1+/Ins+ cells relative to Pdx1+/Inslow cells. Conversely, genes implicated in early β-cell development (MafB, Nkx2.2) were enriched in Pdx1+/Inslow cells. Sorted Pdx1+/Inslow MIN6 cells had a higher replication rate and secreted less insulin relative to double-positive cells. Long-term phenotype tracking of Pdx1+/Inslow cells showed two groups, one that matured into Pdx1+/Ins+ cells and one that remained immature. These results demonstrate that adult β-cells pass through distinct maturation states, which is consistent with previously observed heterogeneity in insulin and Pdx1 expression in adult β-cells. At a given time, a proportion of adult β-cells share similar characteristics to functionally immature embryonic β-cell progenitors. The maturation of adult β-cells recapitulates development in that Pdx1 expression precedes the robust expression of insulin and other mature β-cell genes. These results have implications for harnessing the maturation process for therapeutic purposes.
Type of Medium:
Online Resource
ISSN:
0013-7227
,
1945-7170
DOI:
10.1210/en.2008-1224
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2009
detail.hit.zdb_id:
2011695-0
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