Scientists at the U.S. Food and Drug Administration (FDA) developed an assay that can predict the ability of human mesenchymal stromal cells (hMSCs) to suppress immune system activity.
The study represents an innovative use of morphological features of cells to rapidly predict future cell behavior.
hMSCs are cells derived from multiple tissue sources (such as bone marrow, fat, dental pulp, and umbilical cord) that have the unique ability to give rise to cells associated with bone, cartilage, and adipose tissue. There is also great interest in their ability to suppress unwanted immune system activation.
The FDA finding is important because the ability of hMSCs to suppress immune system responses makes them potentially effective treatments for inflammatory diseases caused by undesirable immune system activities. In the body, activated immune cells (e.g., T cells) can release a substance called interferon-gamma (IFN-gamma), which is typically associated with increased inflammation, but has also been shown to enhance the ability of hMSCs to suppress the immune response.
The immunosuppressive capacity of hMSCs is therefore being investigated as a potential therapy for treating inflammatory diseases such as Crohn’s disease (chronic inflammation of the intestine) and multiple sclerosis (loss of nerve cell signaling function). However, clinical trials studying the use of hMSCs to treat various conditions have not produced reliable, repeatable results. This may be due to the fact that different hMSC lines (i.e., cell populations derived from different donors) can vary significantly in how they function and how strongly they can suppress immune system activity.
Therefore, it is necessary to develop improved methods to reliably predict whether a specific batch of hMSCs will reduce immune activation, which could support efforts to make MSC-based therapeutics more effective and improve patient outcomes. Since current laboratory techniques for doing so are not sufficiently accurate and reliable, the FDA scientists sought to develop a more robust, predictive assay.
The FDA scientists from the Office of Tissues and Advanced Therapies (OTAT) studied the ability of hMSC lines from three different commercial sources to suppress the activity of T cells in cultures. They developed a novel approach that combines sixteen different measures of certain cell surface proteins and T cell growth factors to produce one number that represents the extent of suppression of T cell activity caused by different concentrations of hMSCs from different donors, and hMSCs cultured for extended periods of time (passages).
The scientists then measured over ninety morphological features of hMSCs and found that some morphological changes following stimulation by IFN-gamma were associated with their ability to suppress T cell activity. Interestingly, the morphology of hMSCs not stimulated by IFN-gamma was not useful in predicting immunosuppression. In contrast, the study showed that following stimulation by IFN-gamma, depending on specific changes in multiple features, it was possible to predict how strongly a particular line of hMSCs would be able to suppress T cell activity.
The OTAT scientists previously reported preliminary evidence that it might be possible to use the appearance of specific morphological features of hMSCs to rapidly predict if they will deposit mineralized calcium, a process essential to bone formation.
Together, these results lay the foundation for what the researchers term “functionally-relevant morphological profiling,” which could be used to better characterize hMSC products and potentially facilitate the development of more effective bone and immunosuppressive cell-based therapies.
Morphological features of IFN-γ-stimulated mesenchymal stromal cells predict overall immunosuppressive capacity
PNAS Published online before print March 10, 2017. doi: 10.1073/pnas.1617933114
Matthew W. Klinkera,1, Ross A. Markleina,1, Jessica L. Lo Surdoa, Cheng-Hong Weia, and Steven R. Bauera,2
a Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA 1M.W.K. and R.A.M contributed equally to this work.
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