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题名:Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells.
作者:PENNAROSSA G; MAFFEI S; CAMPAGNOL M; TARANTINI L; GANDOLFI F; BREVINI TA;
来源:Proc Natl Acad Sci U S A. 2013 May 28;110(22):8948-53. doi: [ IF= 0.00 ] ]
URL :10.1073/pnas.1220637110
日期:20130606
摘要:The differentiated state of mature cells of adult organisms is achieved and
maintained through the epigenetic regulation of gene expression, which consists
of several mechanisms including DNA methylation. The advent of induced
pluripotent stem cell technology enabled the conversion of adult cells into any
other cell type passing through a stable pluripotency state. However, indefinite
pluripotency is unphysiological, inherently labile, and makes cells prone to
culture-induced alterations. The direct conversion of one cell type to another
without an intermediate pluripotent stage is also possible but, at present,
requires the viral transfection of appropriate transcription factors, limiting
its therapeutic potential. The aim of this study was to investigate whether it is
possible to achieve the direct conversion of an adult cell by exposing it to a
demethylating agent immediately followed by differentiating culture conditions.
Adult human skin fibroblasts were exposed for 18 h to the DNA methyltransferase
inhibitor 5-azacytidine, followed by a three-step protocol for the induction of
endocrine pancreatic differentiation that lasted 36 d. At the end of this
treatment, 35 +/- 8.9% fibroblasts became pancreatic converted cells that
acquired an epithelial morphology, produced insulin, and then released the
hormone in response to a physiological glucose challenge in vitro. Furthermore,
pancreatic converted cells were able to protect recipient mice against
streptozotocin-induced diabetes, restoring a physiological response to glucose
tolerance tests. This work shows that it is possible to convert adult fibroblasts
into insulin-secreting cells, avoiding both a stable pluripotent stage and any
transgenic modification.

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