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2016
Unchecked mitochondrial DNA mutations could be a problem for stem celltherapies
Mutations accumulate in human mitochondrial DNA with age, reports
a study published April 14in Cell Stem Cell. The finding has
implications for potential therapies using induced
pluripotentstem (iPS) cells, which are generated from patient
skin cells and may be used to repair damaged tissue or organs.
IPS cells derived from an elderly patient's cells could contain faulty
mitochondrial DNA that could undermine the iPScells' therapeutic
value.
As a result, iPS cell lines intended for therapeutic use should be
screened and checked for mitochondrial DNA mutations, say co-senior
authors Shoukhrat Mitalipov, director of the Center for
Embryonic Cell and Gene Therapy at Oregon Health & Science
University, and Taosheng Huang, a medical geneticist and director of the Mitochondrial Medicine Program
at Cincinnati Children's Hospital.
"People tend to look just at the nuclear genome," says Huang. "But if you want to use iPS cells in a human,
you must check for mutations in the mitochondrial genome."
Mitochondrial DNA contains genes that support basic needs, such as energy production for the cell. While
each cell stores two copies of nuclear DNA, there may be a thousand copies of the mitochondrial genome
in a single cell. Those copies can contain both mutated and healthy mitochondrial DNA.
"We call it the freckled effect," says Huang. "Every single cell can be different. Twocells next to each
other could have different mutations or different percentages of mutations."
These mutations can be replicated in iPS cells. Prior to the creation of a therapeutic iPS cell line, a
collection of cells is taken from the patient. These cells will be tested for mutations. If the tester uses
Sanger sequencing, older technology that is not as sensitive as newer next generation sequencing, any
mutation that occurs in less than twenty percent of the sample will go undetected. But mitochondrial DNA
mutations might occur in less than twenty percent of mitochondria in the pooled cells. As a result, mutation
rates have not been well understood. "These mitochondrial mutations are actually hidden," says Mitalipov.
But in the process of making iPS cell lines, researchers expand clones of individualcells from a patient's
biopsy. Every cell in the iPS cell line will contain the same mitochondrial DNA mutations as that initial
adult cell. So rather than studying one iPScell line, Mitalipov and Huang derived and sequenced ten
iPS cell clones from each patient tissue sample to get a better understanding of mitochondrial DNA
mutation rates.
They took samples of blood and skin from people ranging in age from 24 to 72. When they tested the
samples for mitochondrial DNA mutations, the levels of mutations appeared low. But when they
sequenced the iPS cell lines, they found higher numbers of mitochondrial DNA mutations, particularly
in cells from patients over 60. They also found higher percentages of mitochondria containing mutations
within a cell. The higher the load of mutated mitochondrial DNA in a cell, the more compromised thecell's
function.
Since each iPS cell line is created from a different cell, each line may contain different types of
mitochondrial DNA mutations and mutation loads. To choose the least damaged line, the authors
recommend screening multiple lines per patient. "It's a good idea to check the iPS clones for mitochondrial
DNA mutations and make sure you pick a good cell line," says Huang.
The mitochondrial genome is relatively small, containing just 37 genes, so screening should be feasible
using next generation sequencing, says Mitalipov. "It should be relatively cheap and do-able."
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This work was supported by the Leducq Foundation, Oregon Health & Science University institutional
funds and Mayo Clinic Center for Regenerative Medicine and the Cincinnati Children's Hospital Research
Foundation.
Cell Stem Cell, Kang and Wang et al.: "Age-related accumulation of somatic mitochondrial DNA
mutations in adult-derived human iPSCs"http://dx.doi.org/10.1016/j.stem.2016.02.005. Link to the paper
at: http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)00067-9
Related Files
Image 1 & 2: (Credit: Shoukhrat Mitalipov) Confocal microscopy images of human fibroblasts derived
from embryonic stem cells. The nuclei appear in blue, while smaller and more numerous mitochondria
appear in red.
Image 3: (Credit: Shoukhrat Mitalipov) A colony of human induced pluripotent stemcells is shown.
Each cell in the colony is a clone of a single cell taken from an adult human and reprogrammed for
pluripotency.
Author Contacts:
Shoukhrat Mitalipov, Ph.D.
Center for Embryonic Cell and Gene Therapy
Oregon Health & Science University
[email protected]
Office: +1 (503)-418-0196
Taosheng Huang, MD, Ph.D.
Division of Human Genetics
Cincinnati Children's Hospital Medical Center
Office: +1 (513) 803-9260
[email protected]
Media Contacts:
Elizabeth Seaberry
Senior Media Relations Specialist
Oregon Health & Science University
[email protected]
Office: +1 503 494-7986
Mobile: +1 971-806-3579
Terry Loftus
Sr. Director of Public Relations
Cincinnati Children's
[email protected]
+1 513-636-9682 (office)
+1 513-503-7281 (cell)