The rules governing mammalian organ repair and regeneration are so widely varied as to suggest at first glance that there are no rules: Blood has such an enormous regenerative capacity that you can literally give it away by the pint and be none the worse for wear; rip a hole in your skin and new skin will cover it; donate a portion of your liver and it will regenerate; but lose a kidney or suffer damage to your pancreas, and what’s lost is lost.

A new study by Harvard Stem Cell Institute co-director Doug Melton and colleagues published in today’s issue of the journal Nature – and published in advance online – helps to explain the variation both in organ regenerative capacity and in organ size determination as well. The findings also underscore the value of embryonic stem cells as tools to study normal development.

Comparing development of the liver, which can regenerate to compensate for damage, and the pancreas, which cannot, Melton and his team found that the ultimate size and regenerative capacity of certain organs, e.g., the pancreas, is determined by the specific number of progenitor cells that are set aside “during a very early time in development – about day 10 in the mouse. That determines the size of the pancreas for the animal for the rest of its life, and most likely that holds true for humans as well,” said Melton, Thomas Dudley Cabot Professor of the Natural Sciences in the Faculty of Arts and Sciences, and a Howard Hughes Medical Institute Investigator.

Melton said the point of the experiments “was to try to understand how the size of an organ is created. The reason I’m interested in the potential size is that it relates to how the organ can compensate; if you destroy something by disease, why doesn’t it ‘know’ that it’s not the right size any more, and grow back to the right size?

“We knew from the work of other scientists that the pancreas has a very limited, poor capacity for regeneration. So we did experiments where we wanted to control, or fix, the number of progenitor cells during embryogenesis that would make the pancreas. An organ never comes from a single cell; there are a group of progenitors that are set aside, and they and their daughter cells give rise to the organ.”

So Melton, Ben Z. Stanger, and Akemi J. Tanaka asked their questions in two ways. “In one, we took a strain of mouse with no pancreatic progenitors, and then added them back,” Melton explained. “What we found was that when we didn’t add enough back, the pancreas was small. And this was curious, because with blood and other tissues in other embryos, if you remove part of the progenitors for an organ, the embryo ‘realizes’ and compensates. But in this case, a little baby mouse would be born, and all its organs would be just fine, except for the pancreas, which would be half size.

“That made us wonder if the progenitors had a fixed capacity for growth,” he said. “So we then approached the same question from the opposite direction: We began with a normal embryo and we specifically reduced the number of pancreatic progenitors. And again, if we reduced the number to 50 percent of normal, we’d get a half-size pancreas. And the animal can never compensate and develop a normal-size pancreas.” In comparison, when Melton’s team conducted a set of experiments in which the embryonic development of the liver was limited, the organ compensated after birth.

The findings, Melton said, “speak to the general question of why the pancreas is so inefficient at repairing itself and compensating, and this result follows on our result of a few years ago that said there were no adult stem cells” in the pancreas. “So if we take those earlier findings and these, they say that the way your pancreas is made, if you don’t get the right number of progenitors, you’re already in trouble. And then at birth, you have a certain number of insulin-producing pancreatic beta cells, and if you don’t get the right number of insulin-producing beta cells, you’re already in trouble. If you kill them off, as in type 1 diabetes, the organ can’t repair itself.

“I think the work is of interest to people generally because it shows there are different kinds of mechanisms to control size, or tissue mass, for different organ systems. The blood is the classic, well-understood example: There’s an almost infinite capacity to make more blood, and a single, hematopoietic stem cell can make up the entire blood stem. What we’re seeing is that, first of all, the pancreas doesn’t have an adult stem cell, and those that exist in the embryo have a very limited capacity for growth.

“This is another in a long list of examples where embryonic stem cells are extremely useful [in helping us] understand the basic facts about how tissues are made and maintained. We and other scientists using them as a research tool find them extremely important as we study diseases where tissues are not being maintained,” Melton said.