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最近，哈佛大学Doug Melton率领的研究小组和宾州大学医学院Jake Kushner率领的研究小组各自独立发现，胰岛素分泌β细胞的数量是由成体非祖细 Kristen Brennand1,2,3, Danwei Huangfu1,2,3, Doug Melton1,2,3* 1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, United States of America2 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States of America, 3 Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, United States of America
In healthy adult mice, the β cell population is not maintained by stem cells but instead by the replication of differentiated β cells. It is not known, however, whether all β cells contribute equally to growth and maintenance, as it may be that some cells replicate while others do not. Understanding precisely which cells are responsible for β cell replication will inform attempts to expand β cells in vitro, a potential source for cell replacement therapy to treat diabetes. Two experiments were performed to address this issue. First, the level of fluorescence generated by a pulse of histone 2B–green fluorescent protein expression was followed over time to determine how this marker is diluted with cell division; a uniform loss of label across the entire β cell population was observed. Second, clonal analysis of dividing β cells was completed; all clones were of comparable size. These results support the conclusion that the β cell pool is homogeneous with respect to replicative capacity and suggest that all β cells are candidates for in vitro expansion. Given similar observations in the hepatocyte population, we speculate that for tissues lacking an adult stem cell, they are replenished equally by replication of all differentiated cells.
Abbreviations: CAGG, a constitutive promoter containing the CMV enhancer and the chicken β-actin promoter; FACS, fluorescence-activated cell sorter; H2BGFP, histone 2B–green fluorescent protein; LRC, label-retaining cell; MADM, mosaic analysis with double markers; mEF, mouse embryonic fibroblast; mES cell, mouse embryonic stem cell; RIP, rat insulin promoter; rtTA, reverse tetracycline transactivator; tetO, tetracycline-inducible promoter; tTA, tetracycline transactivator.
* To whom correspondence should be addressed. E-mail: dmelton@mcb.harvard.edu
Brennand K. et al.,"All ß cells contribute equally to islet growth and maintenance," PLoS Biology, 5:X-Y, 2007.
Teta M. et al.,"Growth and regeneration of adult ß cells does not involve specialized progenitors," Developmental Cell, 12:817-26, 2007.
全文链接：
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050163
Developmental Cell, Vol 12, 817-826, 08 May 2007
Short Article
Growth and Regeneration of Adult β Cells Does Not Involve Specialized Progenitors
Monica Teta,1 Matthew M. Rankin,1 Simon Y. Long,1 Geneva M. Stein,1 and Jake A. Kushner1,
1 Division of Endocrinology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Corresponding author
Jake A. Kushner
kushnerj@mail.med.upenn.edu
Summary
Cellular progenitors remain poorly characterized in many adult tissues, limited in part by the lack of unbiased techniques to identify progenitors and their progeny. To address this fundamental problem, we developed a novel DNA analog-based lineage-tracing technique to detect multiple rounds of cell division in vivo. Here, we apply this technique to determine the adult lineage mechanism of the insulin-secreting β cells of pancreatic islets, an important unresolved question in diabetes research. As expected, gastrointestinal and skin epithelia involve specialized progenitors that repeatedly divide to give rise to postmitotic cells. In contrast, specialized progenitors do not contribute to adult β cells, not even during acute β cell regeneration. Instead, β cells are the products of uniform self-renewal, slowed by a replication refractory period that prevents β cells from immediately redividing. Our approach provides unbiased resolution of previously inaccessible developmental niches and can elucidate lineage mechanisms without candidate markers.
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