Use stem cells to make insulin-secreting pancreatic beta cells

 

The human body may be genetically inclined to attack its own cells, destroying the beta cells in the pancreas that make insulin, which helps convert sugar into energy
.

This disease, called type 1 diabetes, can occur at any age.

But Xiaojun "Lance" Lian, associate professor of biomedical engineering and biology at Pennsylvania State University, said there may be another personalized option
.

For the first time in the laboratory, Lian and his team used small molecules to convert human stem cells into insulin-producing beta cells, which made the process more efficient and cost-effective

Stem cells can become other types of cells through signals from their surrounding environment, and some mature cells can restore the pluripotency induced by stem cells
.

The researchers found that their method is applicable to human embryonic stem cells and induced pluripotent stem cells, both of which are derived from federally approved stem cell lines

Professor Lian said: "Diabetes is a serious disease in the United States and around the world
.

The patient's own immune cells will kill their own ability to produce insulin and regulate blood sugar levels

Stem cells can become any type of cell through environmental conditions or laboratory interference
.

Professor Lian said that the key is to find the precise conditions that enable the stem cells to transform into the desired cell type

Professor Lian said: “If we can transform stem cells into pancreatic beta cells and transplant them back into patients, it is possible to cure diabetes
.

This is a difficult question to answer.

According to Lian, in previous attempts, researchers used growth factors or proteomes to manipulate stem cells into various types of cells
.

However, the growth factor is expensive and unstable, resulting in high cost and low efficiency of the production process

"In 2012, our team discovered a new molecular mediator that can differentiate stem cells into the mesoderm or endoderm stage.
This is a development point in the process of cell maturation," said Professor Lian, noting that this process uses Small organic molecules, not bigger growth factors
.

"These small molecules are much cheaper and more stable than growth factors.

These small molecules consist of a compound called CHIR99021 (CHIR) and activate a signaling pathway called Wnt, which guides cells into an intermediate type
.
When Wnt is fully activated, the cells become mesoderm and eventually mature heart cells
.
However, a smaller dose of CHIR only partially activates the Wnt pathway, causing endoderm cells to be induced into mature pancreatic cells or hepatocytes
.

"No one else has discovered this because you have to precisely and carefully optimize the CHIR concentration," said first author Yuqian Jiang, a biomedical engineering PhD student in Professor Lian's laboratory
.
"We know that CHIR is important for stem cell differentiation, but other people may only test an off-target concentration of this chemical and think it has no effect
at all.
We tested all possible concentrations and found that it can differentiate stem cells into endoderm.
The precise concentration of cells
.
"

The researchers injected the cells with increasing concentrations of CHIR
.
They found that the lowest dose was not enough to transform the cells, while the high dose completely killed the cells
.
At the second and third low doses, up to 87% of the stem cells became endoderm cells, which can be further guided to become pancreatic cells
.

"The differentiation of beta cells takes about a month, and different chemical mixtures established by previous studies are added in different steps," Jiang said
.
But previous research protocols used growth factors to advance stem cells to endoderm cells
.
Our solution eliminates this need and saves costs while still being able to produce a large number of cells
.
"

The researchers also tested the developed islet cells with glucose
.
Lian said these cells display their functions by producing insulin based on the glucose in their environment
.
In order to prevent the patient's body from killing these cells-which is the primary problem for patients with type 1 diabetes-the researchers plan to encapsulate the modified cells with biomaterial polymers before transplanting the stem cells
.
This can protect the cells while allowing them to sense the surrounding environment and produce the appropriate level of insulin
.

Lian said: "Our method allows us to use the same low-cost chemicals to generate different intermediate cell types at different doses, one of which can become pancreatic cells
.
We are now working to optimize this method and transfer it.
In clinical trials, we have done the hard work to significantly reduce costs
.
Cell therapy is great, but not everyone can afford it
.
Our goal is to make it available to everyone who needs it
.
"

Other contributors include Lian’s laboratory member, Chuanxin Chen, who graduated in 2018 and is currently working at the Bioland Laboratory in China, as well as postdoctoral fellow Lauren N.
Randolph from the Department of Biomedical Engineering and the Harker Institute of Life Sciences and the Department of Chemistry at the Eberly Institute of Science Xin Zhang and Songtao Ye et al
.

Yuqian Jiang, Chuanxin Chen, Lauren N.
Randolph, Songtao Ye, Xin Zhang, Xiaoping Bao, Xiaojun Lance Lian.
Generation of pancreatic progenitors from human pluripotent stem cells by small molecules.
Stem Cell Reports, 2021; DOI: 10.
1016/j.
stemcr .
2021.
07.
021