A TWIST in mesenchymal stem cell trials: protein predicts therapy’s potential

Mesenchymal stem cells are adult stem cells with the potential to specialize into a somewhat limited number of cell types – those responsible for making fat, bone and cartilage. But MSCs are also known for their anti-inflammatory properties which are carried out via the release of protein factors.  This ability to dampen the immune system makes the MSC an extremely attractive source material for cell therapies. In fact, there are over 500  mesenchymal stem cell-based clinical trials testing treatments for diseases that target a wide range of tissues including spinal cord injury, diabetes, multiple sclerosis, respiratory disorders and graft versus host disease, just to name a few.

Human_MSCs_4x_0

Human mesenchymal stem cells grown in a single layer on the bottom of a flask; 4x magnification Image source: EuroStemCell

 MSCs and the Variability Problem
While some MSC-based human trials have had promising results in patients, other studies haven’t been as successful. A key culprit of these mixed results is the lack of standardization on what exactly is a MSC. It’s well documented that preparations of MSC vary significantly from one patient to the next. Even the composition of MSCs from one patient is far from a pure population of cells. And few of the cell surface markers used to define MSCs provide a measure of the cells’ function. This is a real problem for demonstrating the effectiveness and the marketability of MSC-based cell therapies which rely on the delivery of cell product with a consistent, well-defined composition and functional activity.

Help is now on the way based on research reported this week in EBioMedicine by a research team led by Professor Donald Phinney at the Florida campus of The Scripps Research Institute. In the study, the team found that the amount of TWIST1, a protein that regulates gene activity, in a given batch of MSCs could reliably predict the therapeutic effectiveness of those cells.

Meet TWIST1: predictor of a MSC therapy’s potential
They set their sights on TWIST1 because previous research described its important role in driving a MSC fate during human development. The team examined the natural variability of TWIST1 levels in human MSCs from several donors. They showed that lower levels of TWIST1 correlated to MSCs with stronger anti-inflammatory properties. Higher levels of TWIST1, on the other hand, were consistent with MSCs that induced angiogenesis, or blood vessel growth, another known ability of this versatile cell type. In another set of experiments, TWIST1 production was silenced using genetic tools. As predicted by the earlier results, these MSCs showed increased anti-inflammatory properties.

Move over Ritcher, Say Hello to the CLIP Scale

CLIPscale

The Clinical Indication Prediction (CLIP) scale. Image: Boregowda et al. EBioMedicine, Volume 4 , 62-73

Putting this data together, the team devised a scale they call Clinical Indication Prediction, or CLIP for short. The scale gives a clinical researcher an indication of the therapeutic potential of a given batch of donor MSCs based on the TWIST1 protein levels. This information could have a major impact on a clinical trial’s fate. Depending on the goal of a MSC-based cell therapy, a clinical team could set themselves up for failure before the trial even gets underway if they don’t take TWIST1 levels into account. First author Siddaraju V. Boregowda explains this scenario in a press release:

boregowda_siddaraju copy

Siddaraju V. Boregowda

“There are a number of clinical trials testing mesenchymal stem cells to treat arthritis. Since angiogenesis is a key part of the disease process, stem cells with high levels of TWIST1 (indicating they are more angiogenic) would not be beneficial. These cells might be helpful instead for indications such as peripheral vascular disease where new vascularization is beneficial. The proposed CLIP scale accurately predicts these indications and contra-indications.”

We’ll be keeping our eye on this exciting discovery to see if CLIP becomes an integral step in developing MSC-based cell therapies. If it pans out, the CLIP scale could help accelerate the development of new therapies by providing scientists with more clarity and confidence around classifying the identity of a MSC cell product. Stay tuned!

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