Mesenchymal stem cells are the subject of many clinical trials and show a potent ability to down-regulate unwanted immune responses and quell inflammation. A genuine challenge with mesenchymal stem cells (MSCs) is controlling the genes they express and the proteins they secrete.
A new publication details the strategy of one enterprising laboratory to control MSC function. Work by Jeffery Karp from the Harvard Stem Cell Institute and Maneesha Inamdar from the Institute for Stem Cell Biology and Regenerative Medicine in Bangalore, India and their colleagues had use microparticles that are loaded with small molecules and are readily taken up by cultures MSCs.
In this paper, which appeared in Stem Cell Reports (DOI: http://dx.doi.org/10.1016/j.stemcr.2016.05.003), human MSCs were stimulated with a small signaling protein called Tumor Necrosis Factor-alpha (TNF-alpha). TNF-alpha makes MSCs “angry” and they pour out pro-inflammatory molecules upon stimulation with TNF-alpha. However, to these TNF-alpha-stimulated, MSC, Karp and others added tiny microparticles loaded with a small molecule called TPCA-1. TPCA-1 inhibits the NF-κB signaling pathway, which is one of the major signal transduction pathways involved in inflammation.
Delivery of these TPCA-1-containing microparticles thinned-out the production of pro-inflammatory molecules by these TNF-alpha-treated MSCs for at least 6 days. When the culture medium from TPCA-1-loaded MSCs was given to different cell types, the molecules secreted by these cells reduced the recruitment of white blood cells called monocytes. This is indicative of the anti-inflammatory nature of TPCA-1-treated MSCs. The culture medium from these cells also prevented the differentiation of human cardiac fibroblasts into collagen-making cells called “myofibroblasts.” Myofibroblasts lay down the collagen that produces the heart scar after a heart attack. This is a further indication of the anti-inflammatory nature of the molecules made by these TPCA-1-treated MSCs.
These results are important because it shows that MSC activities can be manipulated without gene therapy. It is possible that such non-gene therapy-based approached can be used to fine-tune MSC activity and the types of molecules secreted by implanted MSCs. Furthermore, given the effect of these cells on monocytes and cardiac fibroblasts, perhaps microparticle-treated MSCs can prevent the adverse remodeling that occurs in the heart after a heart attack.