Pancreatic Progenitor Cells—Recent Studies

0013-7227/08/$15.00/0 Printed in U.S.A. Endocrinology 149(9):4312– 4316 Copyright © 2008 by The Endocrine Society doi: 10.1210/en.2008-0546 Minireview: Pancreatic Progenitor Cells—Recent Studies Hsun Teresa Ku Department of Diabetes, Endocrinology, and Metabolism, Beckman Research Institute of City of Hope, Duarte, California 91010 Past studies of pancreatic progenitor cell biology relied mostly on histological analyses. Recent studies, using genetic labeling and tracing of progenitors, direct single cell analyses, colony assays, and enrichment of the minor population of progenitor cells through the use of cell surface markers, have strongly suggested that pancreatic progenitor cells with various frequency and lineage potentials, including the multipotent progenitors that give rise to endocrine, exocrine, and duct cells, exist in the developing and adult pancreas. In this review, it is therefore proposed that pancreatic progenitor cells may be organized in a hierarchy, in which the most primitive pan-pancreatic multipotent progenitors are at the top A FUNCTIONAL PANCREAS consists of two types of tissue: exocrine and endocrine. The exocrine tissue mainly consists of acinar cells, which secrete bicarbonate and digestive enzymes. These secretions are collected by the pancreatic ductal system, which begins with centroacinar cells that are directly in contact with acinar cells. The prolongation of the terminal ducts, or alveoli, are lined by centroacinar cells and gradually merge into a main duct that drains into the duodenum. The endocrine tissue is organized as islets and contains cells that secrete glucagon, insulin, somatostatin, pancreatic polypeptide, or ghrelin (1, 2). These endocrine hormones are released directly into the blood stream in response to metabolic signals. Recently there has been an intense interest in identifying pancreatic stem or progenitor cells, especially the endocrine progenitor cells, for the purpose of replacement therapy of type I diabetes, a disease in which the insulin-secreting ␤-cells are specifically destroyed by autoimmunity. The pancreatic progenitor cell field has slowly evolved over time but has made exciting advances in recent years. This minireview will present a focused perspective of how this field has advanced over the past 10 –15 yr by examining the experimental data available so far and will provide some suggestions as to how this field may move forward in the near future. Progenitor Cell Studies Based on Histological Analysis The first notion of what may constitute an endocrine progenitor population in the pancreas came from histological First Published Online June 5, 2008 Abbreviations: Cpa1, Carboxypeptidase A1; cre, cyclization recombinase; E, embryonic day; Ngn3, neurogenin3; Pdx, pancreatic and duodenal homeobox gene. Endocrinology is published monthly by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community. and rare, and the monopotent progenitors are at the bottom and abundant. This model may explain why only drastic injuries lead to effective activation of the progenitor cell compartment of the higher hierarchy, whereas under steady state, pregnancy, and milder injuries, recruitment of preexisting mature cells or their immediate monopotent progenitors could be sufficient to restore metabolic homeostasis. It is also proposed that the morphologically defined ductal cells are likely to be functionally heterogeneous and that endocrine progenitor cell activity should be determined based on functional analyses rather than histological locations. (Endocrinology 149: 4312– 4316, 2008) studies of developing rodent embryos and regenerating adult pancreases under certain injury models (reviewed in Ref. 3). In the pancreatic progenitor cell field, the terms progenitor cells and stem cells are used interchangeably by some investigators, although the ability of any cell type in the pancreas to self-renew, which is a defining property of true stem cells, has not been vigorously tested. The murine embryonic pancreas, which consists of dorsal and ventral buds, develops from the endoderm-derived duodenal region of the foregut (1, 4). The pancreatic dorsal bud evaginates from the foregut at embryonic day (E) 9.0 of the mouse embryo, and the ventral bud evaginates at E9.5. Histologic and immunohistochemical analyses demonstrate that ductal structures and their branches form by E13.5, and by E17.5 prominent budding islets can be seen adjacent to, or in the vicinity of, the ducts (5). The single cells in the newly formed islets often express multiple combinations of endocrine hormones both in embryos (5–10) and adults (11). Based on these findings, it was proposed that embryonic endocrine progenitor cells originate from the ducts and express multiple hormones before becoming terminally differentiated. Similar to the embryonic pancreas, the ductal cells in adults are thought to be the endocrine progenitor cells, based on histological studies after pancreas injury. In general, long-term regeneration of tissue after injury is indicative of stem cell activity. Several methods that induce pancreas damage have shown endocrine progenitor cell activity in the mature pancreas, including 90% pancreatectomy in rats (12, 13), wrapping a part of the hamster or monkey pancreas with cellophane (14, 15) or a murine autoimmune destruction model for ␤-cells in which ␥-interferon, expressed under the control of the insulin promoter, led to inflammation-induced loss of islets and acinar cells (16). Pulse-chase experiments using bromodeoxyuridine immunohistochemistry (12, 13, 16) or tritiated thymidine autoradiography analyses (14) revealed that proliferation occurs first in the ducts and then in the 4312 Ku • Minireview islets (12, 14), and extensive formation of ducts and budding of islets in the vicinity of the ducts is observed (12–16). Together, these findings led to the conclusion that ductal cells are the progenitors of islets. Progenitor Cell Studies Based on in Vitro and in Vivo Lineage-Tracing Analysis Extrapolating progenitor cell activity with morphological and histological analyses is at most inconclusive, as demonstrated by studies using lineage-tracing strategies and singlecell analyses (to be described in the following sections). Using lineage tracing, or more precisely progenitor tracing, the first theory that was challenged was the germ layer origin of the pancreatic islets. Because endocrine islets express many neuronal genes, it was thought that the endocrine cells were of neuroectodermal origin and migrated into the pancreatic anlage. This hypothesis was disproved through the use of chick/quail (17, 18) and transgenic mouse (19) tissue recombination studies. In the mouse study, early (E11.5) embryonic pancreatic epithelia that were labeled with constitutively expressed ␤-galactosidase were dissected. These epithelia gave rise to both amylase- and insulin-expres (...truncated)