» Articles » PMID: 23696663

Brief Demethylation Step Allows the Conversion of Adult Human Skin Fibroblasts into Insulin-secreting Cells

Overview
Specialty Science
Date 2013 May 23
PMID 23696663
Citations 51
Authors
Affiliations
Soon will be listed here.
Abstract

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.

Citing Articles

Epigenetic memory as crucial contributing factor in directing the differentiation of human iPSC into pancreatic β-cells in vitro.

Diane A, Mu-U-Min R, Al-Siddiqi H Cell Tissue Res. 2025; 399(3):267-276.

PMID: 39883142 PMC: 11870940. DOI: 10.1007/s00441-025-03952-8.


Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells.

Tang P, Wei F, Qiao W, Chen X, Ji C, Yang W Bioact Mater. 2024; 45:181-200.

PMID: 39651397 PMC: 11625219. DOI: 10.1016/j.bioactmat.2024.11.018.


Generation of Artificial Blastoids Combining miR-200-Mediated Reprogramming and Mechanical Cues.

Pennarossa G, Arcuri S, Gandolfi F, Brevini T Cells. 2024; 13(7.

PMID: 38607067 PMC: 11011911. DOI: 10.3390/cells13070628.


Transplantation of Chemical Compound-Induced Cells from Human Fibroblasts Improves Locomotor Recovery in a Spinal Cord Injury Rat Model.

Kurahashi T, Nishime C, Nishinaka E, Komaki Y, Seki F, Urano K Int J Mol Sci. 2023; 24(18).

PMID: 37762156 PMC: 10530737. DOI: 10.3390/ijms241813853.


Use of Epigenetic Cues and Mechanical Stimuli to Generate Blastocyst-Like Structures from Mammalian Skin Dermal Fibroblasts.

Arcuri S, Pennarossa G, Ledda S, Gandolfi F, Brevini T Methods Mol Biol. 2023; 2767:161-173.

PMID: 37199907 DOI: 10.1007/7651_2023_486.


References
1.
Zerbini G, Podesta F, Meregalli G, Deferrari G, Pontremoli R . Fibroblast Na+-Li+ countertransport rate is elevated in essential hypertension. J Hypertens. 2001; 19(7):1263-9. DOI: 10.1097/00004872-200107000-00011. View

2.
Kahan B, Jacobson L, Hullett D, Ochoada J, Oberley T, Lang K . Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation. Diabetes. 2003; 52(8):2016-24. DOI: 10.2337/diabetes.52.8.2016. View

3.
Vignjevic S, Todorovic V, Damjanovic S, Budec M, Mitrovic O, Djikic D . Similar developmental patterns of ghrelin- and glucagon-expressing cells in the human pancreas. Cells Tissues Organs. 2012; 196(4):362-73. DOI: 10.1159/000335469. View

4.
Banga A, Akinci E, Greder L, Dutton J, Slack J . In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proc Natl Acad Sci U S A. 2012; 109(38):15336-41. PMC: 3458366. DOI: 10.1073/pnas.1201701109. View

5.
Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R . Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science. 2001; 292(5520):1389-94. DOI: 10.1126/science.1058866. View