As children age, they get better at doing a lot of things. But growing new beta cells isn’t one of them. In fact, by the time children reach the age of 10 to 12 years, their beta cells have largely lost their ability to divide and make new cells. Now, JDRF-funded researchers at Stanford University have identified a pathway responsible for this age-related decline in beta cell production and have shown that they can coax older beta cells into dividing as frequently as they did when they were younger.
The work, which was published last month as an advance online publication in Nature, provides the most complete picture to date of the molecular gears and levers that bring beta cell regeneration to a near halt. The finding not only paves a path forward for developing strategies to treat type 1 and type 2 diabetes, it also has broader implications for treating aging in general.
“The ability to regenerate damaged or lost tissue declines with age in many tissues in the body, not only in beta cells,” says Seung Kim, M.D., Ph.D., who led the study. “So this is not just a diabetes-specific result—it is part of a greater story of how to treat aging and make older tissues act young again.”
In their work, the researchers systematically tracked the activity of a protein called platelet-derived growth factor (PDGF) across different ages in mice. In young mice, they found that PDGF normally docks on its receptor on the surface of the beta cell and sends a series of signals via the so-called “PDGF pathway” to the cell’s nucleus. These signals instruct beta cells to divide, or form new beta cells. However, the researchers found that, as the mice grew older, the number of PDGF receptors on their beta cells declined or reduced with age. It turns out that without its receptor, PDGF can’t dock and activate the PDGF pathway, and beta cell proliferation is not set in motion.
To further test whether the reduced number of PDGF receptors is behind beta cells’ waning ability to proliferate as they age, the researchers artificially increased the number of PDGF receptors on older beta cells to see if they could restore the cells’ ability to divide and generate new cells. Not only did older beta cells begin to divide in living mice in response to PDGF, but the researchers also observed similar results in human beta cells treated in a Petri dish, suggesting that a drug developed for mice may also work for humans.
“What is exciting about our work is that with the advent of new genetic techniques and the completion of the Human Genome Project, we were able to identify a protein within the beta cell that we can manipulate to get older beta cells to grow and proliferate in a desirable, controlled manner,” says Dr. Kim, who is also a Howard Hughes Medical Institute investigator.
However, it wasn’t always so easy. In the past, researchers have used other techniques to trigger older beta cells to start dividing, but they have been met with consistently frustrating results. “If you tweak other proteins in the cell, a different picture emerges,” says Dr. Kim. “You can get these cells to grow, but they will literally lose their identity. They will either stop making insulin, or they’ll grow just fine but they will grow uncontrollably or into other cell types.”
By better understanding the mechanisms that control and govern how beta cells divide and proliferate, researchers could potentially transform treatments for diabetes, says Patricia Kilian, Ph.D., JDRF’s scientific program director of regeneration research. The cascade of events leading from the beta cell’s surface to its nucleus could inspire scientists with new ideas on how to develop drugs that safely promote the regeneration of beta cells to replace those lost in T1D.