A new article written for the MDC website at https://www.mdc-berlin.de/41851446/en/highlights/
The Spagnoli group at the MDC discovers a crucial step in the development of the pancreas and liver – and how to alter the fates of cells
Remember those time-lapse films in which flowers grow and bloom within seconds rather than weeks? A similar view of a human embryo would reveal some surprises. A fertilized egg divides into daughter cells that form three layers, fold into relatively simple shapes, then undergo intricate feats of “origami” and other processes to produce complex organs. The foregut, for example, begins as a simple tube and later yields the entire upper digestive system, including the liver and pancreas. These organs arise from a common pool of cells. At some point their “parents” acquire features that determine which organ they will become, but scientists have been unable to pinpoint the differences. Now Francesca Spagnoli’s group has identified a molecular signaling pathway that determines the cells’ fates. By activating the pancreatic pathway in the parent population, and even in cells already specialized for the liver, the scientists can trigger their development into pancreatic tissue. The findings, reported in the Sept. 1 issue of Genes & Development, may help scientists develop new treatments for diabetes and other diseases.
“We wanted to know what triggers endoderm cells to form the pancreas rather than the liver,” Francesca says. “Another question was what preserves the identity of these cells once they have differentiated, because the organs share certain functions. Usually cell fates are determined by the activation of unique sets of genes. At that point they produce different RNAs and proteins that alter cell structure and behavior.”
The scientists studied early stages of liver and pancreas development in mice, which provide insights into human organ formation because of the close evolutionary relationship between the two species. They examined cells derived from the foregut of embryos immediately prior to and immediately following the determination of their fates.
Postdoc Elisa Rodríguez-Seguel, with help from other members of Francesca’s lab and particularly Nancy Mah, a bioinformatician in Miguel Andrade’s lab, examined all RNA transcripts expressed in the foregut endoderm. This is the outer layer of the gut tube; its cells form bud-like protrusions that develop into either the liver or pancreas. The sets of RNAs produced by these cells indicated which genes were active at the two points of time.
The experiments revealed that prior to specialization, cells in the endoderm activate genes involved in the noncanonical Wnt pathway. Such signaling networks usually consist of dozens of key molecules that receive information from the environment and pass it into the cell interior, eventually changing the pattern of active and silent genes. One function of the information is to tell cells how to specialize and adopt their proper roles in organs and tissues.
“When the process of differentiation has begun,” Francesca says, “the progenitor cells that will form the pancreas maintain noncanonical Wnt signaling. But it shuts down in cells destined for the liver. At that point it is an either/or situation, and the signals are crucial in maintaining the cells’ identity.”
To test this scenario, the scientists used a molecule called Wnt5 to activate the pathway and observe the effects of the signal on the development of cells. Here they focused on frog embryos, in which noncanonical Wnt has been extensively studied. They followed up with similar studies in mice and embryonic stem cells that have been stimulated to acquire the features of pancreatic cells.
Each case revealed noncanonical Wnt signaling in pancreatic cells, but not in those of the liver. Additionally, the group was able to stimulate the pathway in liver progenitors and partially “reprogram” them to assume the properties of pancreatic tissue.
“Potentially, these findings could be extremely important in the development of new therapies for diabetes and other metabolic diseases,” Francesca says. “Type I diabetes is caused by a loss of the insulin-producing cells in the pancreas, called beta cells. One solution might be to stimulate the noncanonical Wnt pathway in other healthy cells, which could cause them to specialize and replace the beta cells that have been lost.”
The work already represents a major step forward in research into the pancreas and liver. It gives researchers new tools to study the first steps in the development of these organs, and thus to identify what goes wrong when they fail to form in the proper way.
Rodríguez-Seguel E, Mah N, Naumann H, Pongrac IM, Cerdá-Esteban N, Fontaine JF, Wang Y, Chen W, Andrade-Navarro MA, Spagnoli FM. Mutually exclusive signaling signatures define the hepatic and pancreatic progenitor cell lineage divergence. Genes Dev. 2013 Sep 1;27(17):1932-46.