Columbia University Medical Center

5 Questions with Prof. Emmanuelle Passegué on Stem Cells

Emmanuelle Passegué directs the Columbia Stem Cell Initiative

Emmanuelle Passegué, director of the Columbia Stem Cell Initiative. Photo: Columbia University Medical Center.

Cancer, dementia, heart disease: The biggest risk factor for developing these diseases isn’t a specific gene, but increasing age.

“Aging seems to affect organs and tissues across the body in different ways, but when we look closer, we see that the reduction in a tissue’s function that comes with age usually correlates with a reduction in stem cell activity,” says Emmanuelle Passegué, PhD, the new director of the Columbia Stem Cell Initiative. “We’re asking, can we tackle the problem of aging by maintaining stem cell function?”

We spoke with Dr. Passegué just a few weeks after she arrived from the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California San Francisco, where Dr. Passegué has spent the past 11 years.

Q: Tell us about your research into aging – what do stem cells have to do with aging?

A: The effect of stems cells on aging is very important and really starting to emerge from recent research. I work on stem cells and aging in the blood system, but the principles are similar to what happens in the hair follicles that lead to gray hair and hair loss or to what happens in the intestines that lead to digestive problems. We’re seeing that the stem cell is the engine that maintains tissue function, and that’s lost during aging.

In my own lab, we’ve found why blood stem cells acquire mutations over time, which drives a lot of the problems with aging, like losing the power of your immune system. As we get older, we don’t respond to vaccinations or viruses as well, and the resulting infections are a big killer of the elderly. Can we do something here? Can we replace those stem cells and rejuvenate the blood system? Those are the ideas we’re exploring in my lab.

We just published a recent study in Nature showing that a vast majority of aged blood stem cells have changes in their metabolic activity and we are trying to correct that using interventions that stimulate the self-eating process of autophagy.

Aging impairs stem cells that produce our blood cells, causing a wide range of health problems. Cell images from doi:10.1038/nature13619

Q: Is there anything coming out of your research that you think is close to moving toward the clinic?

A: One of my interests in moving to Columbia is to reinforce the lab’s clinical collaborations and move what we are doing in animal models into human samples.

My lab is focused on discovering when and how different types of blood cells are produced and what goes wrong when you have chronic inflammation or cancer, or during aging.

One thing that’s very exciting from a therapeutic standpoint is our work in understanding myeloid malignancies [diseases including myelodysplastic syndromes and acute myeloid leukemia that arise in blood stem or progenitor cells]. In myeloid malignancies, we’ve found that interleukin-6 leads to excessive production of myeloid cells, by reprogramming some progenitor cells, and we’re looking into ways to block it. We also worked on deregulations happening in the bone marrow microenvironment that support the development of myeloid malignancies, including fibrosis, and we are testing ways to prevent this niche remodeling to enhance the fitness of normal blood stem cells and block the function of disease-initiating leukemic stem cells.

Other recent work, using imaging and single cell RNA sequencing, is providing us with a new understanding of normal and diseased myelopoiesis as well as new potential targets for therapeutic interventions. But there is still a lot of work to be done to translate these findings in the clinic.

Leukemia hijacks the normal process of myeloid cell production. Clusters of myeloid progenitor cells (purple) in the bones of normal mice (left) and in mice with leukemia. Images: doi:10.1038/nature21693

Q: About 10 years ago, when the general public thought of stem cell therapies, they envisioned new cells that could replace aged and dysfunctional cells, and it seemed stem cell therapies were just around the corner. What happened?

A: There was a big breakthrough in 2006 when Shinya Yamanaka (who won the Nobel Prize in 2012) showed how we could take skin cells, turn them into induced pluripotent stem cells, and direct them to differentiate into different tissues. That gave us hope that we could replace the neurons that are damaged in Parkinson’s, for example, or create new insulin-secreting cells to help fight diabetes.

This kind of promise is still there, but we’re not as close to therapies as [news articles made it seem]. At that time, the scientific work hadn’t really started.

human ips cells

Human induced pluripotent stem (iPS) cells. Image: Columbia Stem Cell Initiative

Now science has progressed, and we know these stem cells are not fully equivalent to human embryonic stem cells. We know that they keep the imprint of their initial fate, and you would never put these cells in a patient because of the risk of developing a tumor. But they are an incredible tool for research.

When I look back at the stem cell field I know the most–bone marrow transplantation–it took us 50 years to get from the initial scientific discovery of blood-forming stem cells to patients. And for the first 15 years, bone marrow transplants were risky as we worked out the best procedures. Now it’s relatively safe–and it’s the only curative approach for a lot of blood cancers–but there was a long path to get there.

 

Q: Are there stem cell therapies that are close to the clinic?

A: At the moment, retinal replacement is very exciting. You can put embryonic stem cells in a dish and turn them into retinal cells that can re-create the retina. And then you can transplant the retinal cells into a blind patient. That’s going forward very well, but there are still a lot of challenges: What kind of biomaterial can we embed the cells in? What are the safest procedures?

Beta cells for diabetes are also exciting. Unlike the blood system, we don’t need a fully mature pancreas cell to get insulin production. We still have to figure out what’s the most efficient and cost-effective way to derive the beta cells: Is it better to take cells from a cadaver or make them from embryonic stem cells? How can we prevent the immune system from rejecting these new cells?

And these cells are not drugs so they will require a different kind of regulation before they can be used in people.

 

Q: You just started your new role as director of the Columbia Stem Cell Initiative? What are your initial plans?

A: We have a very strong community here at Columbia. One of the first things I’m doing is organizing a TED-style event where investigators with an interest in stem cell research give 15-minute talks about their interests. Then I can see what overarching themes are emerging and what I can do to build on what’s already here.

I’m also putting together an array of facilities to support the work of the investigators. We have an outstanding stem cell facility here, and I’m adding a flow cytometry facility that will allow researchers to really isolate the stem cell from the rest of the body’s tissue. Everything researchers do in the lab to understand stem cells–or edit the cell’s genes with CRISPR/Cas9–requires isolating them.

In addition, I’m looking to recruit new, young researchers–at the top of their fields–to build on and complement what’s going on in the program.

By next year, we should have our program nucleus set up in the Black Building, and my mission is to gather the rich scientific community here on campus into one of the most active stem cell programs in the country.

 

The Columbia Stem Cell Initiative was launched in 2008 to bring together researchers to explore the potential of using stem cells to improve human health. The initiative’s membership includes researchers and clinicians in stem cell-related fields from more than 30 departments on Columbia’s Medical Center and Morningside campuses.