Dr. Taby Ahsan talks animatedly about the intersection of biomechanics and stem cell research in tissue engineering. She would like to know how stem cells from donors of different ages respond to the challenge of complex mechanical cues.
One application is in the area of myocardial infarction, in which there is ischemic heart injury. There have been clinical trials injecting cells from the bone marrow, called mesenchymal stem cells (MSCs), into the heart tissue after a heart attack. These cells have been shown to help restore oxygen delivery to the damaged heart tissue. In cases of those who have heart attacks, and classically the older population are known to have heart attacks, if the heart attack victim is given stem cells from their own body, there is the advantage of avoiding immune rejection of the transplanted cells. This use of stem cells from one’s own body is an example of personalized medicine. However, in this older population this therapy is not as successful as would be expected. Now, with hearts beating about once a second and pumping about 5 liters per minute, it is a very dynamic, complex and severe mechanical environment.
So this raises the question: “If the MCS are implanted into the harsh environment of cardiac tissue, are cells from an older donor able to survive and then promote revascularization of the tissue as well as cells from donors at a younger age?”
One way to test how well these donor cells do in response to mechanical cues is to use bioreactors in which you can isolate the cells and impose mechanical forces they would experience in the heart, such as tension or compression and examine how they respond in terms of viability, proliferation and their ability to differentiate. “These MSC are unique because of their potential to differentiate and become other cells. This potential may be something that is more sensitive to change than the survival of the cell alone.”
Dr. Ahsan believes it is important when transplanting stem cells that they respond appropriately to the micro-environment to help promote the healing effect you would want in the case of myocardial infarction and to cause revascularization of heart tissue. The way cells respond to physical and mechanical input is called mechano-transduction. Mechano-transduction consists of several phases. A sensor converts the external cue into an intracellular signal which might include membrane proteins called integrins or cell adhesion molecules known as selectins that are often trans-membrane proteins. These membrane proteins form complexes with the cyto-skeleton inside the cell, which transmits the signal to the nuclear membrane. Proteins on the nuclear membrane transmit the signal further, and the original mechanical cue thus alters the pattern of gene transcription in the nucleus.
“As we get older what happens to our stem cells?” The body has stem cells in most tissues including fat tissue and bone marrow. As individuals begin to get older there are changes in the number of those types of cells as they get “used up,” repairing and regenerating various minor defects as we age. “Are the stem cells in a 70, 80 or 90 year old as effective at regeneration as those same stem cells in the same location in a 20 year old?” There’s a question of quantity. As we begin to extend the average lifetime, do we have enough of these cells throughout life to induce the repair? Then there’s quality. Do they remain functionally active as we age? She states: “As we age, the cells are exposed to a lot of different cues, which may cause them to become ‘fatigued’.” Perhaps stem cells from older donors are no longer capable of performing the same amount of repair and regeneration as those from younger donors.
Dr. Ahsan was asked how her research can help the aging community. She responded: “We need to identify the transition during aging when stem cells lose the ability to repair and regenerate, if such a clear transition exists. Then our research would shift to a more generic approach, using stem cells from a universal donor. For example, if a 75 year-old has a heart attack instead of using their own cells we would use the cells from a 20 year-old in our therapy.” However, using cells from a universal donor raises compatibility issues, even though it would make the stem cells more readily available. “In the process, we may be able to identify what aspect of the aging stem cell makes it less functional, and thus it may be possible to reverse it with genetic or cell engineering in order to recover that functionality.”
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