Breakthrough Discoveries Inside a TSRI Stem Cell Lab

By Madeline McCurry-Schmidt

Associate Professor Kristin Baldwin and her lab members at The Scripps Research Institute (TSRI) are uncovering the hidden powers of stem cells. Now the team’s latest study, published in the journal Nature Biotechnology and co-led by Ali Torkamani, director of genome informatics at the Scripps Translational Science Institute (STSI), shows that stem cells derived from elderly people may be valuable tools for studying degenerative diseases and developing regenerative treatments for patients of all ages.

“A key finding of this study is that we can take blood cells from highly aged people, even centenarians, and reverse their cell type and apparent age back to a stage that looks like an early embryonic cell, which was surprising to us,” said Baldwin, who is also a member of the Dorris Neuroscience Center at TSRI.

The new study also gives researchers a better look at how cells accumulate mutations over time. “We were also the first to report some signs of the patient’s age that remain in the stem cells, though many of these could be further erased by growing the cells in culture,” Baldwin explained.

A Look Inside the Lab

Baldwin’s lab focuses on induced pluripotent stem cells (iPSCs), cells derived from adult tissue, which her team has learned to reprogram into other cell types, including neurons.

Baldwin and her colleagues believe iPSCs from elderly people are important to study for two main reasons: First, elderly people are the ones most likely to be suffering from degenerative diseases, such as Alzheimer’s or Parkinson’s. If doctors can generate healthy brain cells from an Alzheimer’s patient, for example, they may be able to provide a treatment using that patient’s own cells. Second, elderly people can provide a comprehensive medical history, meaning their cells can be used as controls in scientific studies comparing diseased and healthy cells.

Clearly, stem cells hold a lot of potential. The challenge is to find the best cell lines for future studies and therapies.

TSRI Research Associate Valentina Lo Sardo and Research Assistant Will Ferguson of the Baldwin lab spearheaded the reprogramming work for the new study. They started with blood cells donated by research subjects as part of the STSI “Wellderly” study, an ongoing effort to study the genomes of healthy people who have lived to between 80 and 105 years old. The study then expanded to include cells from the STSI GeneHeart Study and the TSRI research blood donor program, giving the researchers a chance to compare iPSCs from donors of different ages.

Developing multiple iPSC lines from dozens of donors turned out to be a huge undertaking. Lo Sardo and Ferguson worked to pick out and culture the most promising cell colonies. This meant many work days and weekends sitting under sterile hoods, monitoring cell cultures and scraping away potential contaminants. “You have to give your cultures a lot of TLC,” said Ferguson.

On top of that, the researchers knew these cells would need to be screened for potential mutations, so they had to reprogram the cells using a tool called a non-integrating vector, which would be less likely to alter the genome compared with viral vectors that integrate their own genetic material into a cell.

Because previous research had shown that a cell type called a fibroblast becomes harder to reprogram as it gets older, the scientists in this study were surprised to find that cells from older donors were no harder to reprogram than those from younger subjects.

The Next Steps for Older Cells

Meanwhile, researchers in Torkamani’s lab at STSI were developing tools to analyze the genomes of these iPSC lines. Their goal was to study whether cells from elderly people accumulated more mutations, which can pose a potential risk of cancer-linked genetic changes and other issues.

The researchers found that, as they predicted, cells sourced from older donors had gained more mutations linearly over time. Compared with donors in their 20s, iPSC lines generated from donors in their 80s showed twice as many mutations in protein-encoding genes.

“Any time a cell divides, there is a risk of a mutation occurring. Over time, those risks multiply,” Torkamani said. “Our study highlights that increased risk of mutations in iPSCs made from older donors of source cells.”

This doesn’t mean iPSCs from older donors are necessarily dangerous. The researchers are unsure whether these mutations pose a significant risk to cell function.

The study does suggest that cells from older donors should be thoroughly screened before being used in regenerative therapies. “Let’s make sure we pick the best iPSC lines for stem cell therapies,” said Lo Sardo.

The iPSC lines from the new study are also proving to be a valuable resource in the Baldwin lab, giving researchers a diverse library of cells to choose from for future research. Already, iPSC lines from the study are being used to study coronary artery disease and in a graduate student’s project to study cells with a mutation that can influence nicotine addiction.

For more on this research, see the “Influence of donor age on induced pluripotent stem cells” in Nature Biotechnology and the “Research Highlights” article in Nature Methods.

For more on the Baldwin lab’s work, visit the lab website.

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