JDRF Research
Signals From Mouse Pancreas Show Human Stem Cells the Way
JDRF-funded researchers in Sweden have found a process to help turn human embryonic stem cells into the types of specialized cells that have the potential to become treatments for people with type 1 diabetes. A team at Lund University has noted that in the cellular environment of an embryonic mouse pancreas, human stem cells can be coaxed into becoming mature cells that resemble pancreatic beta cells.
If the researchers can tease apart the biochemical interactions involved, they may eventually be able to create an unlimited source of beta cells to replace the insulin-secreting cells lost to diabetes.
The finding, published in the October issue of the journal Diabetes, represents an important step toward creating an unlimited source of beta cells for patients with type 1 diabetes.
IMPORTANCE OF THE NICHE
The scientists’ view — held by an increasing number of stem cell researchers — is that the cellular environment, or “niche”, is of primary importance to embryonic stem cell differentiation. As stem cells develop, the researchers suggest, they engage in constant crosstalk with other cells in the niche, but researchers are unsure of the location or timing of the signals that enable stem cells to develop into their final state.
Researchers have found that conventional methods of inducing stem cells to become beta cells — exposing them to signals in a lab dish — have not been very successful. Some stem cells do become pancreatic progenitor cells, a more primitive form of full-fledged pancreatic beta cells, but they are pale imitations of true beta cells. They don’t produce insulin, and they lack important characteristics needed to regulate blood sugar if they were to be transplanted into someone with diabetes.
The new stem-cell niche approach is to place the pancreatic progenitor cells into an in vivo system (such as a mouse) and let nature take over. Even though the researchers may not understand the process or be able to precisely identify the factors involved, they see that “ecological” interactions are central to a stem cell’s specialization into a pancreatic beta cell. Once they have found a reliable method in vivo, the scientists can try to unravel the signals that help define the characteristics of the stem cell niche so they can be reproduced in a laboratory.
CELLULAR CROSSTALK
For the Diabetes study, the Lund University scientists, led by Henrik Semb, M.D., Ph.D., mixed human pancreatic progenitor cells with pieces of mouse embryonic pancreatic tissue and implanted them beneath the kidney of immune-deficient mice. The immune-deficient mice, called SCID mice (for severe combined immunodeficiency), did not reject the transplant and simply served as incubators so the stem cells could develop within a living organism.
Inside the SCID mice, some of the implanted human progenitor cells developed into cells that evidenced several important hallmarks of beta cells. They synthesized insulin using the usual building blocks and by turning on the genes that regulate beta cell development and function. According to the research team, it appears that exposure to the transplanted mouse pancreas and other signals inside the SCID mouse made the critical difference.
The importance of the mouse embryonic pancreatic tissue as a signal source was confirmed by control experiments. When the researchers transplanted human embryonic stem cells alone into SCID mice, the stem cells did not become beta-like cells. The same lack of development occurred if the human stem cells were transplanted along with mouse embryonic brain or liver cells. The researchers concluded that only pancreatic cells can provide the necessary signals to spur the stem cells down the correct path.
Recreating the different interactions found in nature is no easy task. Dr. Semb and his colleagues say several important questions must be addressed through further research. The scientists don’t know exactly when the pancreatic cell signals come into play, or what the signals consist of. Presumably, the signals turn genes in the stem cells on or off at specific times to guide them correctly. But researchers need to identify the factors that flip the switches. Even if researchers identify these factors, they may determine that stem cells in a lab dish need to be surrounded by other pancreatic precursor cells in order to develop properly.