New beta cells without stem cells?

Adult non-progenitor cells maintain the population of insulin-secreting ￟ cells, according to two papers published this month. The findings, produced by two independent groups led by Doug Melton at Harvard University and Jake Kushner at the University of Pennsylvania School of Medicine, contradict a popular hypothesis that ￟ cell regeneration relies on specialized progenitor cells.

Melton's study appears in the June issue of PLoS Biology, and Kushner's paper is in the May issue of Developmental Cell.

The data are very convincing, but do not exclude the possibility that a small amount of progenitor cells help regenerate ￟ cells, Gladys Teitelman at State University of New York, told The Scientist."If you are looking for rare cells that could participate in regeneration, it would be hard to find them," said Teitelman, who has found evidence of ￟ cell precursor cells in islets after toxic injury to the pancreas.

"So should we call off the search for stem cells in the pancreas? I don't think so," Malcolm Alison, at Queen Mary's School for Medicine and Dentistry in London, wrote in an Email to The Scientist.

Researchers have proposed several sources of ￟ cell regeneration, including stem cells in the pancreas, bone marrow, or pancreatic ducts, and exocrine pancreas cells that could trans-differentiate. In 2004 Melton published data showing ￟ cells arose from pre-existing ￟ cells."Still, this theory has remained very controversial," Kushner told The Scientist.

The two groups came to the same conclusion using different techniques. Kushner's group relied on sequential thymidine labeling, where animals ingested two dividing-cell markers at different periods. The researchers designated cells that incorporated both markers as derived from progenitor cells, since the cells went through multiple rounds of division. Those that incorporated only one marker -- and therefore only divided once -- were considered self-renewing.

"We were shocked to find no specialized progenitor cells," Kushner told The Scientist. Nearly no ￟ cells contained both markers. Instead, it appears that ￟ cells only undergo cell division at specific times, Kushner said, because even when the researchers administered both markers over a period of weeks, ￟ cells contained only one marker -- demonstrating those cells had divided only once during that time period.

Melton's group followed the process by tracking the decay of a fluorescent label as a cell goes through divisions, and the incorporation of a green fluorescent protein (GFP) tag during phases of recombination. Both assays confirmed that pre-existing ￟ cells were the source of new ￟ cells, not adult stem cells. The fluorescent label faded uniformly across ￟ cells, and GFP tags indicated cells recombined during G0 or G1 phases of the cell cycle,"which is expected for a slow-dividing cell population," the authors write.

Melton agreed that progenitor cells may still exist in the pancreas."This study does not disprove it," he told The Scientist."If they do exist they do not contribute appreciably" to islet growth and maintenance.

In the liver, stem cells from the bile ducts become activated following injury, and some researchers propose stem cells might also be lying in wait in the pancreatic ducts."So if we could exclusively block only ￟-cell regeneration in the damaged pancreas, a ductal or indeed other intrapancreatic stem cell may yet show its face," suggested Alison, who studies stem cell biology.

The findings could contribute to the search for diabetes treatments, by helping develop techniques that replenish the body's stock of ￟ cells, Kushner suggested. But researchers still have a long way to go, Melton noted -- although the studies suggest how ￟ cells replicate, they do not address what regulates their division."If we want to replace them," Melton said,"we should understand what's controlling replication rate."

Kerry Grens
mail@the-scientist.com

Links within this article:

Doug Melton
http://www.mcb.harvard.edu/Faculty/Melton.html

Jake Kushner
http://www.med.upenn.edu/camb/faculty/cbp/kushner.html

Bonner-Weir, S."Life and death of the pancreatic beta cells," Trends Endocrinology and Metabolism, 11:375-8, 2000.
http://www.the-scientist.com/pubmed/11042468

Brennand K. et al.,"All ￟ cells contribute equally to islet growth and maintenance," PLoS Biology, 5:X-Y, 2007.
http://biology.plosjournals.org/perlserv/?request=index-html&issn=1545-7885

Teta M. et al.,"Growth and regeneration of adult ￟ cells does not involve specialized progenitors," Developmental Cell, 12:817-26, 2007.
http://www.the-scientist.com/pubmed/17488631

Gladys Teitelman
http://www.hscbklyn.edu/anatomy/teitelman.html

Guz Y. et al.,"Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes," Endocrinology, 142:4956-68, 2001.
http://www.the-scientist.com/pubmed/11606464

L. Defrancesco,"￟ stem cells: Searching for the diabetic's holy grail," The Scientist, October 29, 2001.
http://www.the-scientist.com/article/display/12678

Malcolm Alison
http://www.icms.qmul.ac.uk/Profiles/Diabetes/Alison%20Malcolm.htm

Gershengorn M.C. et al.,"Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells," Science, 306:2261-4, 2004.
http://www.the-scientist.com/pubmed/15564314

Dor Y. et al.,"Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation," Nature, 429:41-6, 2004.
http://www.the-scientist.com/pubmed/15129273

A. Harding,"Harvard has human cloning plans," The Scientist, October 15, 2004
http://www.the-scientist.com/article/display/22452

Bonner-Weir, S,"Islet growth and development in the adult," Journal of Molecular Endocrinology, 24:297-302, 2000.
http://www.the-scientist.com/pubmed/10828822

A. M. J. Shapiro,"Transplanting islets for diabetes," The Scientist, May 2006.
http://www.the-scientist.com/article/display/23394