Researchers have revealed how to transform stem cells into more mature types of cells using small molecules rather than expensive growth factors. Their results were published in a paper today (Aug. 26). Yuqian Jiang was the first to publish the paper. He illustrated the way. Credit: Yuqian Jiang / Penn State
Humans can be genetically inclined towards attacking their own cells. This includes the beta cells of the pancreas, which make insulin and help convert sugar into energy. Type 1 diabetes can strike at any age, and it can lead to death if not managed properly with insulin shots or an insulin pump that balances the body's sugar levels.
According to Penn State associate professor of biomedical and biological engineering, Xiaojun Lian, there might be a better, more personal option. Lian and his team transformed human embryonic stem cells into beta cells that can produce insulin. This was a first-of-its kind.
Stem cells can transform into other types of cells by absorbing signals from their environment. Some mature cells may also revert back to stem cells-induced pluripotency. Their approach was successful for both human embryonic stem cells and induced pluripotent stem cell, which were both derived from federally-approved stem cell lines. Lian believes that their method could be used to reduce or eliminate the demand for embryonic stem cells from humans in the future.
Lian stated that diabetes is a serious disease both in the United States of America and worldwide. "The patient's immune cells destroy their ability to regulate their glucose levels and produce insulin." We believed stem cells could be a solution and allow the patient to control their insulin and glucose levels again.
Through laboratory interference or environmental conditions, stem cells can transform into any type of cell. Lian explained that the trick is to determine the conditions necessary to make a stem cell function as the desired type of cell.
Lian stated that it was possible to cure diabetes if stem cells could be converted into pancreatic beta cells by transferring them back to patients. "It's a difficult question. For more than 20 years scientists have tried to find the answer. Our lab recognized that we needed a new approach.
According to Lian, previous attempts used growth factors (or groups of proteins) to manipulate stem cells to create different cell types. However, growth factors are costly and unstable and can lead to inefficient manufacturing.
Lian stated that in 2012, a new molecular mediator was discovered by Lian. It could differentiate stem cells to mesoderm and endoderm stages. These are points of development along the path to mature cells. These small molecules are cheaper and more stable than growth factor, so we could still replicate the effects of growth factors to differentiate stem cell to intermediate stages.
Researchers at Penn State tested different concentrations of small molecules (CH), which are inexpensive and easy to store, to induce stem cells to become more mature. The cells were tagged with red (mCherry) and died at higher levels over time. Credit: Xiaojun "Lance" Lian / Penn State
These small molecules make up a chemical compound called CHIR99021, or CHIR. They activate Wnt's signaling pathway which directs cells to one of the intermediate types. The cell is transformed into a mesoderm and then a mature heart cell when Wnt activation is complete. A smaller amount of CHIR activates Wnt but only partially. This results in an endoderm that can be converted into a mature liver cell or pancreatic beta cell.
Yuqian Jiang (a biomedical engineering doctoral candidate in Lian's laboratory) said that no one else had discovered this. "You have to carefully and precisely optimize the CHIR concentration." We know that CHIR is essential for stem cell differentiation. However, others may test only one concentration of this chemical to determine if it doesn't work. We tried all concentrations to find the one that differentiated stem cells into endoderm.
Researchers gave increasing amounts of CHIR to cells. The researchers tested the effects of increasing CHIR concentrations on cells. They found that the lowest dose failed to convert cells. Higher doses caused the cells to die. The second and third-lowest doses resulted in 87% of stem cells becoming endoderm cells, which could then be guided to become pancreatic beta cell.
Jiang stated that beta cell differentiation takes approximately a month and can be assisted by different chemical cocktails based on previous research. Previous protocols used growth factors to increase stem cells to become endoderm cells. This protocol eliminates the need for growth factors, saves money and still produces a lot of cells.
Researchers also tested the beta cells in vitro with glucose. Lian stated that the cells made insulin according to glucose levels in their environment. This demonstrated their functionality. These cells can be saved from death by the researchers. Lian said that this would preserve the cells, while still allowing them access to their environment and to make the appropriate amounts of insulin.
Lian stated that the approach allowed them to use the same low cost chemical in different doses to create different types of intermediate cells, one of which could become pancreatic beta cell. We are now optimizing this approach and moving it to clinical trials. However, we have done the hard work to significantly lower the cost. Although cell therapy is an amazing treatment, not everyone can afford it. We want to make cell therapy affordable for everyone.
Lian is also affiliated with the Huck Institute of the Life Sciences.
Andrew Read, director of the Huck Institutes of the Life Sciences, said that Lance's talk about his plans was astonishing. His work is a perfect example of the type of science that seeks to change the game. He has reached an important milestone. It's a great honor.
Learn more about Beta cells from stem cell: Potential for cell replacement therapy
More information: Yuqian Jiang and al, Generation of pancreatic precursors from human pluripotent stem cell lines by small molecules, Stem Cell Reports (2021). Information from Stem Cell Reports Yuqian Jiang and colleagues, Generation of pancreatic precursors from human pluripotent stem cell cells using small molecules, (2021). DOI: 10.1016/j.stemcr.2021.07.021
