Age-associated mitochondrial mutations may scupper iPSC success

Written by Alexandra Thompson

Researchers from Oregon Health & Science University (OR, USA) have found hidden genetic mutations within the mitochondria of patient-derived stem cells, accumulating as the donor has aged, which could have a detrimental effect on therapeutic benefit of any derived cell therapies or regenerative medicines.

Mitochondrial genes are prone to damage as they reside outside of the nucleus. Mitochondrial DNA (mtDNA) mutations arise randomly within individual cells as we age, and can negatively affect cells’ ability to create energy, produce signals and function properly.

Scientists from Oregon Health & Science University (OR, USA) have provided the first evidence towards proving the long-standing theory that aging results in the accumulation of genetic mutations in mitochondria. The promise of iPSCs for treating diseases and damage in humans, being stem cells derived from patients or donors, could therefore be hampered.

“Pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age-related diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at younger age to ensure their mitochondrial genes are healthy,” explained Dr Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon and leader of research team and the first scientist to demonstrate the successful use of somatic cell nuclear transfer (SCNT) to produce human ESCs from skin. “This foundational knowledge of how cells are damaged in the natural process of aging may help to illuminate the role of mutated mitochondria in degenerative disease.”

The scientists derived and sequenced 10 iPSC clones from each patient’s blood and skin; from healthy people and those with degenerative diseases, aged from 24 to 72 years. They then profiled 10 blood cell- and 10 skin cell-derived iPSC lines per patient and sequenced them, upon which they identified higher numbers of mtDNA mutations and mitochondria containing mutations in those derived from more elderly people. The higher the load of mutated mtDNA in a cell, the greater the cell’s function is compromised, but blood cell-derived cells were less likely to have mutations.

As the mutations could potentially hinder the ability of iPSCs to repair damaged tissue or organs, the team advised iPSCs are screened for mtDNA mutations before use. “If you want to use iPS cells in a human, you must check for mutations in the mitochondrial genome,” stated Dr Taosheng Huang, a medical geneticist and director of the Mitochondrial Disorders Program at Cincinnati Children’s Hospital Medical Center (OH, USA). “Every single cell can be different. Two cells next to each other could have different mutations or different percentages of mutations.”

Study co-author Dr Andre Terzic, director of the Mayo Clinic Center for
Regenerative Medicine, commented: “This collaborative multi-disciplinary
effort identifies ‘mitochondrial genome integrity’ as a vital readout
in assessing the proficiency of patient-derived regenerative products
destined for clinical applications.

The results of this study could mean those currently looking to develop iPSC-based cell therapies may need to go back and screen their cells for mtDNA mutations. Furthermore, Mitalipov has also suggested that these results could support the use of SCNT-derived hESCs, however the difficulty in generating these cells would need to be balanced against whether or not they are clinically better than thorough, routine iPSC screening.

Sources: Kang E, Wang X, Tippner-Hedges R et al. Age-related accumulation of mitochondrial DNA mutations in adult-derived human iPSCs. Cell Stem Cell doi:10.1016/j.stem.2016.02.005 (2016) (In Press Corrected Proof);

We recently highlighted the news that researchers at the Wellcome Trust Sanger Institute (UK) have tracked the genetic mutations gathered by iPSCs as they are reprogrammed, and found that none of the mutations occurred in cancer-linked genes and that they should therefore be safe for therapeutic use. This new research however suggests that those currently looking to develop iPSC-based cell therapies may need to go back and screen their cells for mtDNA mutations, as mtDNA mutations, if present, could affect their efficacy as well as safety. What protocols do you think should be established to ensure iPSC safety and efficacy? Or do you think other cell types should be used instead? Tell us your thoughts in the comments!