Stem Cells
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First published online September 21, 2006
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2006-0109v1
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Submitted on February 25, 2006
Accepted on August 22, 2006

Tissue-Specific Stem Cells

Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells

Tayaramma Thatava 1*, Bin Ma 1, Manfred Rhode 2, Hubert Mayer 1

1 Department of Gene Regulation and Differentiation, German Research Center for Biotechnology, Braunschweig, Germany
2 Department of Microbial Pathogenesis, German Research Center for Biotechnology, Braunschweig, Germany

* To whom correspondence should be addressed. E-mail: tth{at}gbf.de.


  Abstract

Type 1 diabetes is caused by the destruction of pancreatic {beta}-cells by T cells of the immune system. Islet transplantation is a promising therapy for diabetes mellitus. Bone marrow stem cells (BMSC) have the capacity to differentiate into various cell lineages including endocrine cells of the pancreas. To investigate the conditions that allow BMSC to differentiate into insulin-producing cells, a novel in vitro method was developed by using the histone deacetylase inhibitor (HDACi), Trichostatin A (TSA). BMSC, cultured in presence of TSA, differentiated into islet-like clusters under appropriate culture conditions. These islet-like clusters were similar to the cells of the islets of the pancreas. The islet-like clusters showed endocrine gene expression typical for pancreatic {beta}-cell development and function, such as insulin (I and II), glucagon, somatostatin, GLUT-2, pancreatic duodenal homeobox-1 (PDX-1), and Pax 4. Immunocytochemistry confirmed islet-like clusters contained pancreatic hormones. The co-localization of insulin and C-peptide was also observed. Enzyme-linked immunosorbent assay (ELISA) analysis demonstrated that insulin secretion was regulated by glucose. Western blot analysis demonstrated the presence of stored insulin. Electron microscopy of the islet-like cells revealed an ultrastructure similar to that of pancreatic {beta}-cells, which contain insulin granules within secretory vesicles. These findings suggest that histone-deacetylating agents could allow the differentiation of BMSC into insulin-producing beta cells.

Key Words. Bone marrow, histone deacetylation inhibitors, Trichostatin A, insulin-producing cells, diabetes




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B. Davani, L. Ikonomou, B. M. Raaka, E. Geras-Raaka, R. A. Morton, B. Marcus-Samuels, and M. C. Gershengorn
Human Islet-Derived Precursor Cells Are Mesenchymal Stromal Cells That Differentiate and Mature to Hormone-Expressing Cells In Vivo
Stem Cells, December 1, 2007; 25(12): 3215 - 3222.
[Abstract] [Full Text] [PDF]


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