Electron micrograph of a human mesenchymal stem cells (Image credit: Robert M. Hunt)

A cell for all therapies
Type “mesenchymal stem cells” into the federal online database of registered clinical trials, and you’ll get a sprawling list of 527 trials testing treatments for diabetes, multiple sclerosis as well as diseases of the kidney, lung, and heart, to name just a few. Mesenchymal stem cells (MSCs) have the capacity to specialize into bone, cartilage, muscle and fat cells but their popularity as a therapeutic agent mostly comes from their ability to reduce inflammation and to help repair tissues.

MSCs may be great tools for scientists to fight disease, but what is it about their natural function that make MSCs – as UC Davis researcher Jan Nolta likes to calls them – the body’s “paramedics”? A fascinating study reported yesterday in Nature Communications by scientists at the Florida campus of The Scripps Research Institute (TSRI) and the University of Pittsburgh suggest that it’s a trait the cells gain as a result of their complex cell survival mechanisms.

The TSRI team came to this conclusion by studying how MSCs respond to oxygen-related stress. MSCs reside in the bone marrow where they help maintain and regulate blood stem cells. The bone marrow is naturally a hypoxic, or low oxygen, environment. Growing MSCs in the lab at oxygen levels found in the air we breathe are much higher than what is found in the marrow. This creates oxidative stress in which the excess oxygen leads to unwanted chemical reactions which disrupt a cell’s molecules.

One cell’s trash is another’s treasure
One result of this oxidative stress is damage to the MSCs’ mitochondria, structures responsible for generating the energy needs of a cell. The team found that MSCs package the faulty mitochondria into sacs, or vesicles, which travel to the cell surface to be dumped out of the cell. At this point, another resident of the bone marrow comes into the picture: the macrophage. Previous research has shown that macrophages and MSCs work closely together to maintain the health of the blood stem cells in the bone marrow.

White arrow shows vesicles (red) carrying mitochondra (green) to the surface of the MSC  and being ingested by a macrophage (round shape in lower half) – (From Fig 2 Nat Commun. 2015 Oct 7;6:8472)

In a high oxygen stress environment, the team observed that MSCs can recruit macrophages to engulf the damaged mitochondria-containing vesicles and repurpose them for their own use. In fact, the researchers measured improved energy production in the macrophages after ingesting the MSCs’ mitochondria. Blocking the transfer of the damaged mitochondria from MSCs to macrophages caused the MSCs to die, confirming that this off-loading of mitochondria to macrophages is critical for MSC survival.

Evolving tricks for cell survival
Macrophages (macro=big; phages=eaters), key players of the immune system and the inflammation response, also rid the body of invading bacteria or damaged cells by devouring them. To avoid being swallowed up by the macrophage while donating its mitochondria, the stressed MSCs have another trick up their sleeve. The research team identified the release of other vesicles from the MSCs that contain molecules called microRNAs which stimulate anti-inflammatory properties in the macrophages. This prevented the macrophages from attacking and eating the MSCs.

And there you have it: as a result of relying on macrophages to survive stressful environments, MSCs appear to have evolved anti-inflammatory activities that turn out to be a handy tool for numerous ongoing and future cell therapy trials.

In a TSRI press release picked up by Newswise, professor Donald Phinney co-leader of study points out the groundbreaking aspect of the study:

Donald Phinney (photo: TSRI)

“This is the first time anyone has shown how mesenchymal stem cells provide for their own survival by recruiting and then suppressing normal macrophage activity.”