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Posts Tagged ‘Islets of Langerhans’


Reporter: Ritu Saxena, Ph.D.

Diabetes currently affects more than 336 million people worldwide, with healthcare costs by diabetes and its complications of up to $612 million per day in the US alone.  The islets of Langerhans, miniature endocrine organs within the pancreas, are essential regulators of blood glucose homeostasis and play a key role in the pathogenesis of diabetes.  Islets of Langerhans are composed of several types of endocrine cells.  The α- and β-cells are the most abundant and also the most important in that they secrete hormones (glucagon and insulin, respectively) crucial for glucose homeostasis (Bosco D, et al, Diabetes, May 2010;59(5):1202-10).

Diabetes is a ‘bihormonal’ disease, involving both insulin deficiency and excess glucagon.  For decades, insulin deficiency was considered to be the sole reason for diabetes; however, recent studies emphasize excess glucagon as an important part of diabetes etiology.  Thus, insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development.  Increasing the number of insulin-producing β cells while decreasing the number of glucagon-producing α cells, either in vitro in donor pancreatic islets before transplantation into type 1 diabetics or in vivo in type 2 diabetics, is a promising therapeutic avenue.  A huge leap has been taken in this direction by the researchers at the University of Pennsylvania (Philadelphia, PA) in collaboration with Oregon Health and Science University (Portland, OR), USA by demonstrating that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets.  In fact, the treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets.  The research findings were published in the Journal of Clinical Investigation.

Study design: First step was to study and analyze the epigenetic and transcriptional landscape of human pancreatic human pancreatic α, β, and exocrine cells using ChIP and RNA sequencing.  Study design for determination of the transcriptome and differential histone marks included the dispersion and FACS to of human islets to obtain cell populations highly enriched for α, β, and exocrine (duct and acinar) cells.  Then, chromatin was prepared for ChIP analysis using antibodies for histone modifications, H3K4me3 (represents gene activation) and H3K27me3 (represents gene repression).  RNA-Sequencing analysis was then performed to determine mRNA and lncRNA.  Sample purity was confirmed using qRT-PCR of insulin and glucagon expression levels of the individual α and β cell population revealing high sample purity.

Results:

  • Long noncoding transcripts: Long noncoding RNA molecules have been implicated as important developmental regulators, cell lineage allocators, and contributors to disease development.  The authors discovered 12 cell–specific and 5 α cell–specific noncoding (lnc) transcripts, indicative of the valuable research resource represented from transcriptome data.  Recently discovered lncRNA molecules in islets are regulated during development and dysregulated in type 2 diabetic islets.
  • Monovalent histone modification landscapes shared among three cell types:  Monovalent H3K4me3-enriched regions, indicative of gene activation, were identified and compared in α, β, and exocrine cells.  Strikingly, the vast majority of monovalently H3K4me3-marked genes were shared among the 3 pancreatic cell lineages (83%–95%), reflecting both their related function in protein secretion and common embryonic descent. Similarly, a high degree of overlap was observed in H3K27me3 modification patterns in all the three cell types (73%–83%).
  • Bivalent histone modifications (H3K4me3 and H3K27me3) were high in α cells: Bernstein colleagues observed bivalent marks to be common in undifferentiated cells, such as ES cells and pluripotent progenitor cells, and in most cases, one of the histone modification marks was lost during differentiation, accompanying lineage specification (Bernstein BE, et al, Cell, 21 Apr 2006; 125(2):315-26).  α cells exhibited many more genes bivalently marked, followed by β cells and exocrine cells.  Bivalent state was remarkably similar to that of hESC, suggesting a more plastic epigenomic state for α cells.
  • Monovalent histone modifications were high in β cells: Thousands of the genes that were in bivalent state in α cells were in a monovalent state, carrying only the activating or repressing mark.
  • Inhibition of histone methyltransferases led to partial cell-fate conversion: Adenosine dialdehye (Adox), a drug that interferes with histone methylation and decreases H3K27me3, when administered in human islet tissue, led to decrease of H3K27me3 enrichment at the 3 gene loci that are originally expressed bivalently in α cells and monovalently in β cells:  MAFA, PDX1 and ARX.  Adox resulted in the occasional cooccurrence of glucagon and insulin granules within the same islet cell, which was not observed in untreated islets.  Thus, inhibition of histone methyltransferases leads to partial endocrine cell-fate conversion.

Conclusion:  α cells have been reprogrammed into β cell fate in various mouse models.  The reason, as proposed by the authors, might be the presence of more bivalently marked genes that confers a more plastic epigenomic state of the cells that probably drives them to the β cell fate.  Therefore, using epigenomic information of different cell types in pancreatic islets and harnessing it for subsequent manipulation of their epigenetic signature could be utilized to reprogram cells and hence provide a path for diabetes therapy.

Source: Bramswig NC, et al, Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest, 22 Feb 2013. pii: 66514.

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Reporter: Aviva Lev-Ari, PhD, RN

New Life – The Healing Promise of Stem Cells

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Diseases and conditions where stem cell treatment is promising or emerging. Source: Wikipedia
Since the late 1990s, the Technion has been at the forefront of stem-cell research. Stem cells are the master keys because they can be converted into many different kinds of cells, opening many different doors to potential cures and treatments. Beating heart tissue is one of the major stem cell achievements from the Technion.
Healing the Heart
 
Technion scientists showed this year that they can turn skin tissue from heart attack patients into fresh, beating heart cells in a first step towards a new therapy for the condition. The procedure may eventually help scores of people who survive heart attacks but are severely debilitated by damage to the organ.
By creating new heart cells from a patient’s own tissues, doctors avoid the risk of the cells being rejected by the immune system once they are transplanted.Though the cells were not considered safe enough to put back into patients, they appeared healthy in the laboratory and beat in time with other cells in animal models.
“We have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage his heart cells were in when he was just born,” Prof. Lior Gepstein told the British national paper The Guardian.

Pancreatic Tissue for Diabetes

Prof. Shulamit Levenberg of the Technion, who has spent many years trying to create replacement human organs by building them up on a “scaffold,” has created tissue from the insulin-producing islets of Langerhans in the pancreas surrounded by a three-dimensional network of blood vessels.The tissue she and her team created has significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

“We have shown that the three-dimensional environment and the engineered blood vessels support the islets – and this support is important for the survival of the islets and for their insulin secretion activity”, says Prof. Levenberg of the Department of Biomedical Engineering.

In the Bones

BonusBio - Health News - Israel


In collaboration with industry and global research partners, Technion scientists have grown human bone from stem cells in a laboratory. The development opens the way for patients to have broken bones repaired or even replaced with entire new ones grown outside the body from a patient’s own cells. The researchers started with stem cells taken from fat tissue. It took around a month to grow them into sections of fully-formed living human bone up to a couple of inches long. The success was reported by the UK national paper The Telegraph.

Stem Cell Proliferation

““These are our next generation of scientists and Nobel Laureates,” says Prof. Dror Seliktar, of the Department of Biomedical Engineering. “The future of the Technion relies on that.”

Seliktar and his research team at the Lokey Center for Biomaterials and Tissue Regeneration at Technion is working on a new material for the mass production of stem cells to make their commercial use viable on an industrial scale.

“In the biotechnology industries, there is an inherent need for expanding populations of stem cells for therapeutic purposes,” says Seliktar, who has published over 50 papers in the field, won over 14 awards and launched one of Israel’s promising biotech startups, Regentis Biomaterials.

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Prof. Joseph Itskovitz-Eldor of the Faculty of Medicine was on the international team that in 1998 first discovered the potential of stem cells to form any kind of tissue and pioneered stem-cell technology. The breakthrough garnered headlines around the world. He is the Director of the Technion Stem Cell Center.

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Other posts on this Scientific Web Site about innovations completed on this topic at the Technion are cited below:

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