What are the mechanisms that regulate organ size in vertebrates? And to what extent is size determined by cell-autonomous (intrinsic) and non-cell-autonomous (extrinsic) mechanisms? Douglas Melton and colleagues now show that two closely related endoderm derivatives, the pancreas and the liver, use different strategies for determining their final size.

"...two closely related endoderm derivatives, the pancreas and the liver, use different strategies for determining their final size."

Melton and co-workers combined two different methods — cell ablation and tissue complementation — to perturb the number of precursor cells during the earliest stages of pancreatic and liver development. Pancreatic progenitor cells, which express the transcription factor Pdx1 during development, were eliminated during pregnancy. Embryos that lacked any Pdx1⁺ progenitors were virtually apancreatic. By contrast, pancreases from embryos that had a normal complement of Pdx1⁺ progenitors throughout pregnancy exhibited a normal appearance and preserved weight.

So, does pancreatic progenitor cell growth follow an autonomous programme? Or are there other factors involved? To address these questions, Melton and colleagues postulated that a chimaeric embryo derived from combining Pdx1-deficient blastocysts with wild-type embryonic stem (ES) cells would exhibit selective growth and maturation of ES progeny during pancreatic development. Indeed, the pancreas was formed entirely from donor ES cells in this system. Although the majority of chimaeras generated from Pdx1^-/- blastocysts contained some pancreatic tissue, significant variation in pancreatic size was observed — the greater the contribution of ES cells, the larger the pancreas. Taken together, the above findings indicate that a limited number of pancreatic progenitor cells might naturally undergo only a precise number of cell divisions. The limited cell divisions would set the size of the organ, and these cells would therefore have more difficulty in regenerating organ tissue during adult life.

Do other organs develop with similar growth mechanisms? The authors examined the liver, which is also derived from the endoderm. But in contrast to the pancreas, the liver undergoes regeneration following injury or partial removal. Ablation of hepatic progenitor cells through embryonic day E13.5 resulted in a 65% reduction in the hepatic progenitor cell pool. However, four days after an initial pulse of ablation, liver size was back to normal.

The authors therefore propose that there are two kinds of tissue in vertebrates: "Tissues, like the liver, that exhibit regulated growth in development and robust regeneration in adulthood owing to extrinsic signals, and others, like the pancreas, that exhibit reduced regenerative capacity in adulthood because of intrinsic growth constraints that are imprinted early in development." The nature of these intrinsic constraints remains to be determined.

Author: Ekat Kritikou - Copyright © 2007 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission