Scientists at the U.S. Food and Drug Administration (FDA) have developed a strategy that may improve the ability to identify batches of cells with a particular desired function for use as human therapies.
These cells, called mesenchymal stromal cells (MSCs), respond to substances called growth factors. Following treatment by growth factors, MSCs can turn into cells that form cartilage, bone, or fat. This response makes the cells potentially useful for regenerating or restoring tissues in the body. Also, certain growth factors stimulate MSCs so they can help the body control inflammation by suppressing immune cell functions. Suppression of the immune system might be useful for treating immune disorders such as Crohn’s disease (chronic inflammation of the intestine) and multiple sclerosis (loss of nerve cell function due to immune reactions against nerve cells).
The new technique, called functionally-relevant morphological profiling (FRMP), enabled the FDA scientists to predict how much a population of stimulated MSCs would be able to suppress key types of immune cells. This prediction is based on the appearance of distinct changes in cell shape that happen after MSCs are exposed to a growth factor called interferon-gamma (IFN-gamma).
The development of FRMP is important because it could help scientists more readily identify which MSC batches will be safe and effective. This information will also help scientists refine their manufacturing methods to make MSCs more consistent and reliable. Moreover, FRMP might be useful for figuring out how other types of cells respond to a variety of different growth factors.
In the new study, the FDA scientists showed for the first time that INF-gamma triggers different levels of immunosuppressive activity in different batches of MSCs, as measured in cell-based studies. That is, the MSCs in large batches do not all respond to stimulation in a coordinated way to produce effective immunosuppressive activity. Rather, many of them have not developed immunosuppressive activity or are at various stages in developing that activity.
Prior research suggests that this uncoordinated response of specific MSC batches to stimulation is due to several factors, e.g., using MSCs from different donors and different sources (e.g., fat tissue, blood, or bone marrow), as well as differences in manufacturing. The FDA scientists developed the new technique to tell the difference between stimulated MSCs that have the most immunosuppressive activity from those that have lesser amounts of activity.
This is a novel strategy that could help overcome complications in preparing safe and effective MSC-based therapies for a variety of diseases.
Morphological profiling using machine learning reveals emergent subpopulations of interferon-γ–stimulated mesenchymal stromal cells that predict immunosuppression
Cytotherapy, 2019;21: 17-31
Ross A. Marklein1,2, Matthew W. Klinker1, Katherine A. Drake3, Hannah G. Polikowsky3, Elizabeth C. Lessey-Morillon1, & Steven R. Bauer1/
1Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA, 2School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA, and 3Cytobank, Inc., Mountain View, California, USA