Making Beta Cells

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A skin cell by any other name would be as fleshy—or so you might think. But a new technique developed over the last decade can take skin cells, or any other cells of the body, and make them into something new. This process, being probed by the lab of Rohit Kulkarni, M.D., Ph.D., Senior Investigator in the Section on Islet Cell and Regenerative Biology at Joslin Diabetes Center, holds promise for the damaged pancreas of people with diabetes.

Induced pluripotent stem cells, or iPSCs for short, have the remarkable power to become anything in the human body. Unlike the more familiar embryonic stem cell, iPSCs once lived day-today as any normal skin cells would. Until one day they get plucked from the surface of the body and brought into a lab. After some tinkering, they find themselves reverted back to what they were before they became skin cells, back to the early stem cell state. This process gives IPSCs the chance to do it all over again—they can become anything in the human body.

What are iPS cells?
Being full of all these possibilities is known as “pluripotency.” This pluripotency is induced by processes in a lab. And so, we get induced pluripotent stem cells—iPSCs.

The scientific community used to believe that once a cell grew up (or differentiated, in scientific lingo), it sealed its fate; a skin cell couldn’t change its mind, go back to the stem cell state (or dedifferentiate) and suddenly become a cell of the heart, for example.

But in 2006 a Japanese scientist named Shinya Yamanaka figured out how to catalyze this reversion to a stem cell state in a lab, using certain proteins that reprogram the cell at a molecular level.

“So they started with 24 of these reprogramming factors, removed them one by one and they eventually found that four of them, the infamous Yamanaka factors, can actually generate iPS cells,” said Adrian Teo, Ph.D., Post-Doc in Dr. Kulkarni’s lab.

Cells for iPSC creation can come from a skin biopsy or a blood sample. Then, researchers bathe their harvest in a solution full of the Yamanaka factors for about a month, until enough iPSCs emerge. Once in their stem cell state, researchers begin to push them forward again into whatever cells they need: insulin-secreting beta cells, in the case of Dr. Kulkarni’s lab at Joslin.

iPS cells

“We are really interested in understanding why diabetes occurs in different populations,” said Dr. Teo, who focuses his post-doc research in this area.

iPS in the Lab
The Kulkarni lab currently has cell collections from 30 or 40 individuals with different types of diabetes. Some of Dr. Teo’s work focuses on cells from people with type 1 and type 2 diabetes. He and his colleagues are trying to make iPSCs become insulin-secreting beta cells. Once that happens, they can compare the growth of the diabetic cells to non-diabetic cells to see exactly where the default in development occurs.

“What we want to do is to derive sufficient numbers of these beta cells from type 1 and type 2 diabetic patients and then subject them to different types of drugs and chemical compounds to see for example if we can induce more beta cell proliferation for instance, or maybe retard or inhibit the insulin resistance phenotype in type 2 diabetic patients,” he said.

Pushing iPSCs to become insulin secreting beta cells is a seven stage process, mirroring the growth of beta cells in normal developmental biology. To make beta cells, they start with iPSCs and introduce different combinations of molecular compounds until the cells move forward one step. They continue until all seven stages are complete, leaving them with a functional beta cell. So far, they’ve made it up to stage five.

“The tedious process is trying to find the precise cocktail of those compounds which are able to push it from stage five to stage six with high efficiency,” said Dr. Kulkarni. “Once we find that particular magic compound then that will allow us to move forward at a much more rapid rate.”

Aside from the cells from people with type 1 and type 2 diabetes that are in the works, Dr. Kulkarni’s lab has already published research on MODY, which is a type of diabetes caused by a single gene mutation. There are many different types of MODY, but in most cases people develop diabetes by the age of 25.

In a collaboration with a lab in Norway, they compared the cells from three family members—one with no MODY mutation at all, one with the mutation but no diabetes, and one with the mutation who has developed diabetes.

“We derived iPS cells from different types of MODY patients—MODY 1, 2, 3, 5, and 8. And we’re in the process of differentiating these iPS cells towards pancreatic cells,” said Dr. Teo. Along the way, they are finding that some of the MODY mutated genes are important in the growth of the pancreas. “At a stage when this gene is important for the development, we see a defect when you compare iPS cells from MODY patients versus a family member without the mutation,” he continued.

Dr. Teo working in the lab of Dr. Kulkarni

By monitoring the development of these cells from three different individuals, Dr. Teo and others in Dr. Kulkarni’s lab can understand how the disease progresses. And they are looking into the possibility of fixing the MODY mutated gene in the lab, and then putting the “corrected” cell back into the affected individual.

How Can iPS Cells Help?
Dr. Kulkarni isn’t alone at Joslin. Other labs, such as the Diane Nunnally Hoppes Laboratory for Diabetes Complications led by Dr. George King, are looking at ways to treat complications with iPSCs by trying to create liver, kidney, heart, and nervous system cells out of skin cells.

“I want to emphasize the opportunity of using iPS cells because cell types such as those that make up the pancreas, liver, heart, eye, kidney or brain in living patients are not easily accessible for research,” said Dr. Kulkarni. “So one cannot go and take a small part of the heart cell or the nervous system, but the iPS cell allows us to derive these important cell types for investigation and make it a very unique resource which would otherwise not be possible.”

iPSC differentiation could also lead to personalized medicine. Each cell holds the genetic code of the person it was taken from; doctors could screen each individual’s cells to see which medical intervention method they’ll best respond to, avoiding the trial and error method employed for prescribing drugs today.

But ideally, iPSCs would be used to erase the need for medications altogether.

“The long term goal would be to create large numbers of these cell types at the bench and put them back into the patient exactly where the disease is occurring,” said Dr. Kulkarni. “For example in patients with diabetes we want to have a large bank of insulin secreting beta cells which are derived from the patient’s iPS cells and then we want to put those cells back into the pancreas where they belong.”

Because these cells would have their root in the patient, their transplantation could avoid the host rejection issues inherent in other transplant options currently available.

More labs at Joslin are looking at treatment of obesity, insulin resistance, and skeletal muscle dystrophy with iPSC techniques.

“This iPS cell field is moving very fast and a lot of exciting work is progressing at the moment,” said Dr. Teo.

“The Joslin has made it a major initiative by undertaking it at a very early stage,” said Dr. Kulkarni. “We think that Joslin is going to make a major effort in advancing this field.”

To learn more about research at Joslin, visit Joslinresearch.org

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