Six-Month Project Update
Human pluripotent stem cell (hPSC)-derived pancreatic β cells are attractive cell sources for treating diabetes. However, current derivation methods are still inefficient, heterogeneous, and cell line dependent, suggesting yet unknown mechanisms or signaling pathways are involved. We first devised a new strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered a novel combination of chemicals not only retaining the pancreatic progenitors in 3D clusters but also enhancing their propensity towards β cells. Based on this, we are now identifying stepwise chemical components through systematic screening of pathway modulators to efficiently differentiate pancreatic progenitors into β cells. Implementation of all these new strategies and chemical combinations may result in an unprecedented high efficiency of generating β cells from different sources of hPSCs facilitating their clinical translation.
Currently, the best treatment for T1D is the transplantation of pancreatic beta cells (in the form of pancreatic islet) from a donor. However, pancreas donations are extremely limited. Human stem cells multiply infinitely and differentiate into different cell types that can be used in cell replacement therapy, providing new hope for curing T1D. After more than 15 years of continual endeavor, scientists have successfully converted human stem cells into functional insulin-producing pancreatic beta cells. The stem cell-derived pancreatic beta cells have been demonstrated to cure T1D in experimental animals. In fact, stem cell-derived pancreatic beta cells are very close to being used in the clinic to treat patients.
However, before we can use stem cell-derived pancreatic beta cells in the clinic, we first have to overcome three problems:
- Safety issue: tumors are frequently observed after transplantation of certain types of human stem cells.
- High Cost: The current seven-step process is expensive.
- Time-consuming: The seven-step protocol takes more than one month to complete.
My strategy is to improve the generation of pancreatic beta cells in a safe and cost-effective way. I also intend to generate the entire human pancreas by injecting intermediate pancreatic cells into pancreas-deficient animal embryos (such as rabbit and sheep). Since the experimental animal embryo can’t develop a pancreas, the human pancreatic cells may fill the developmental gap and form a human pancreas in the animal.
Expectations from the project:
- Development of purified pancreatic progenitors or later stage cells, that only generate pancreatic cells, thereby preventing the potential for tumor formation.
- Reduce the process from 7 steps to 1-3 steps, enhancing the stability of the cells and greatly reducing time and cost.
- Making beta cells in bulk which is more efficient and suitable for clinical applications.