August 3, 2020

The Niche

Knoepfler lab stem cell blog

New Mitalipov paper on stem cell mitochondria: challenge for IPS cell field?

A new paper from Shoukhrat Mitalipov’s lab on stem cell mitochondria points to a pattern whereby induced pluripotent stem (IPS) cells tend to have more problems if they are from older patients.

What does this paper mean for the stem cell field and could it impact more specifically the clinical applications of IPS cells?

Mitalipov mitochondrial mutations
Graphical Abstract, Kang, et al. 2016

The new paper Kang, et al is entitled “Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs”.

This paper reminds us of the very important realities that mitochondria are key players in stem cell function and that mitochondria have their own genomes that impact that function. A lot of us don’t think about mitochondria and their genome as often as we should.

The paper came to three major scientific conclusions (this from the Highlights section of the paper and also see the graphical abstract for a visual sense of the results overall):

  • Human iPSC clones derived from elderly adults show accumulation of mtDNA mutations
  • Fewer mtDNA mutations are present in ESCs and iPSCs derived from younger adults
  • Accumulated mtDNA mutations can impact metabolic function in iPSCs

Importantly the team looked at IPS cells derived from both blood and skin cells and found that the former were less likely to have mitochondrial mutations.

This study suggests that those teams producing or working with human IPS cells (hIPSCs) should be screening the different lines for mitochondrial mutations. This excellent piece from Sara Reardon on the Mitalipov paper quotes IPS cell expert Jeanne Loring on this very point:

“It’s one of those things most of us don’t think about,” says Jeanne Loring, a stem-cell biologist at the Scripps Research Institute in La Jolla, California. Her lab is working towards using iPS cells to treat Parkinson’s disease, and Loring now plans to go back and examine the mitochondria in her cell lines. She suspects that it will be fairly easy for researchers to screen cells for use in therapies.”

Mitalipov goes further and suggests that his team’s new findings could support the use of human embryonic stem cells (hESC) derived by somatic cell nuclear transfer (SCNT) which would be expected to have mitochondria with fewer mutations. However, as Loring points out in the Reardon article, SCNT is really difficult to successfully perform and only a few labs in the world can do it at present. In that context, working with hIPSC and adding on the additional layer of mitochondrial DNA mutation screening could be more practical.

New York stem cell researcher Dieter Egli, however, is quoted that hIPSC have other differences with hESC as well such as epigenetic differences and he’s quoted in the Reardon piece, “It’s going to be very hard to find a cell line that’s perfect.”

One might reasonably ask both Egli and oneself, “What is a perfect cell line?”

In the end the best approach for use of human pluripotent stem cells of any kind is going to involve a balance between practicality of production and the potentially positive or negative traits of those cells as determined by rigorous validation screening.

With this new paper we’ve just learned more about another layer of screening that is needed. An interesting question is whether adult stem cells such as mesenchymal stromal/stem cells (MSC) also should be screened for mitochondrial mutations. They are often produced from patients who are getting up there in years. I hope that someone will publish on that too.

As to pluripotent cells, I expect that sometimes the best lines, meaning those most perfect for a given clinical application, will be hIPSC (autologous or allogeneic in some instances) and in other cases they may be hESC made from leftover IVF embryos. If SCNT-derived hESC can be more widely produced in an affordable manner and they pass validation as well then those (sometimes called NT-hESC) may also come into play clinically. So far that hasn’t happened for the SCNT cells, but it may over time.

The more types of pluripotent cells and indeed stem cells more generally including adult stem cells that we have in our clinical arsenal to help patients the better as long as the cells and any derivatives made from them have gone through vigorous validation in each case and there’s hard data to support their use in patients with a reasonable expectation of both safety and efficacy going into any particular clinical study.

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