New studies are providing key insights into the progenitor cells that give rise to different cell types in the pancreas. Both type 1 and type 2 diabetes are characterized by loss of functional beta cells, the pancreatic cells that produce the hormone insulin. Strategies to repopulate beta cells, either by transplant or by induction of new beta cell formation, show promise in treating diabetes. Toward successful therapeutic strategies, scientists are making progress in identifying, characterizing, and understanding the factors and mechanisms that underlie pancreatic development. In addition to the insulin-producing beta cells, the pancreas is composed of multiple other cell types. Some of these—like beta cells—produce hormones released into the blood to regulate the body’s metabolism; these cell types are termed “endocrine.” Other cell types produce proteins that aid in the digestion of food; these cell types are termed “exocrine.” In order to promote the formation of new beta cells, scientists, including members of the NIDDK-supported Beta Cell Biology Consortium, are determining when and how certain pancreatic progenitor cells become “committed” to developing into specific endocrine or exocrine cell types.
In one study, scientists investigated the role of a group of proteins, called presenilins, in specifying pancreatic cell types in mice. They studied cells that have Ngn3, a well-established marker of embryonic pancreatic progenitor cells, and discovered that the activity of presenilins was needed to block the cells from becoming exocrine cells. This showed that Ngn3 was not sufficient to commit pancreatic progenitor cells to endocrine cell types. Rather, cells that have Ngn3 can become endocrine or exocrine cells—a flexibility of Ngn3 cells that was previously unknown. In a second study, using elegant labeling techniques to mark a single mouse pancreatic progenitor cell and monitor its progression, another group of scientists focused on the Ngn3 cells that become endocrine cells and found that these cells are “unipotent” precursors. That is, Ngn3 is a marker shared in common by cells destined to develop into different endocrine cell types, but each individual Ngn3-containing cell is committed to becoming only one of the endocrine cell types. In fact, unlike other progenitor cells that proliferate to generate many mature cells, Ngn3-containing cells often appeared not to proliferate at all, with each one simply morphing into its final endocrine cell type. These findings are important because understanding the characteristics of progenitor cells that can turn into beta cells can help inform new strategies toward generating new beta cells to replace those impaired by diabetes.
In a final study, scientists uncovered additional plasticity in a pancreatic endocrine cell type—the alpha cell. Using genetic techniques in mice, the researchers increased the levels of a protein called Pax4, which is known to be involved in promoting cells to develop into endocrine cell types. They found that mice with high levels of Pax4 had oversized clusters of beta cells, which resulted from alpha-beta precursor cells and established alpha cells being induced to form beta cells. In addition, in a mouse model of diabetes, the high levels of Pax4 promoted generation of new beta cells and overcame the diabetic state. The discovery that alpha cells have the potential to convert to beta cells, and the additional insights on pancreatic progenitor cells made in the other studies, generate a fuller picture of pancreatic development. These advances may pave the way toward new cell-based therapies for diabetes.
Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H, and Mansouri A: The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells in alpha and subsequently beta cells. Cell 138: 449-462, 2009.
Cras-Méneur C, Li L, Kopan R, and Permutt MA: Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window. Genes Dev 23: 2088-2101, 2009.
Desgraz R and Herrera PL: Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Dev 136: 3567-3574, 2009.