MSCs on Display
There is an illustration (aka cartoon) that Celling Biosciences commissioned for a review article written by Drs. Matthew Murphy, Katy Moncivais and Arnold Caplan. Dr. Caplan, Director of the Skeletal Research Center at Case Western Reserve University (Cleveland, OH), is one of the icons in the stem cell biology world due to his many publications over the years that have greatly expanded our knowledge and understanding of developmental skeletal biology, stem cell biology, the role of stem cells in natural healing and translating that knowledge into meaningful cell-based therapies. Drs. Murphy and Moncivais are colleagues of mine at Celling Biosciences and are in training to be future icons of translational cell-based therapy.The cartoon to which I refer is shown below this paragraph. I would like to review the essential features of the cartoon, since it contains nearly all that you need to know about what mesenchymal stem cells (MSC) are and what they are thought to do in vivo. We will start in the upper left corner.
As shown in the upper left corner, Dr. Caplan has long contended that MSCs exist in tissue primarily as cells called “pericytes”, which are progenitor cells attached to the outside of blood vessels—known as the perivascular space. I had the privilege of working with Dr. Caplan when I was at Vet-Stem, Inc. on a study of the correlation of the frequency of MSCs and blood vessel density in equine adipose tissue. So, MSCs can be found in the perivascular space of blood vessels in bone marrow, fat and other vascularized tissues.
As shown in the cartoon, the quiescent pericytes can be activated by responding to soluble distress signals that are known to be released as a result of a “deviation from homeostasis.” Examples of deviations from homeostasis include broken bones, torn cartilage, soft tissue strains and, my favorite, controlled pathologies also known as surgery. In other words, whenever the body is not in homeostatic balance, there are responses to the imbalance that collectively are known as the natural healing process.
So, the triggering incident has occurred, signals have been sent out and the pericytes become mobile. Is it just me, or do pericytes being found along vascular structures seem to be the ideal location for cells that respond to signals spreading through the blood stream and then mobilizing and migrating, also via the blood stream, to the incident pathology? I also want to give a shout out to the lymphatic system as another possible superhighway for migrating MSCs, although I have no proof of that assertion. It just makes sense to me, since there is a roller derby of cellular activity going on all the time in the lymphatic system, especially in lymph nodes, which are connected by lymphatic vessels.
As indicated in the cartoon, after activation, the pericytes mobilize in the form of a MSC. These activated MSCs proceed to migrate and subsequently home in on the site of pathology. In the old days, it was thought that once the cells implanted at the site of pathology they would differentiate into whatever the adult tissue cells were at that site (e.g., chondrocytes in articular tissue). Of course, we now know that engraftment and MSC differentiation into adult tissue cells isn’t a primary mechanism for regenerating tissue in most cases. In fact, once the MSCs (and other progenitor cells, like endothelial progenitor cells or EPCs) arrive at their destination they begin to assert their presence by responding to the microenvironment in a multitude of ways. I will cover these effector functions of MSCs (highlighted in the center of the cartoon) in the next post.