Human heart with age, gradually loses its capacity to repair itself after injury. Damage caused by heart attack and cardiac ischemia is due to low oxygen levels in heart. Hence, making it difficult to perform daily activities as heart function decreases below normal capacity. To boost heart repair after ischemic injury, scientist have turned to stem cell-based therapies to replace dead heart tissue with a new functional one. However, in many cases, less than 1% stem cells survive heart transplant. This is due to the inability to cope with metabolic demands of heart.
Expressing LIN28 in Cardiac Stem Cells
Research suggest that stem cell-based therapies can pave way to reduce this problem. Researchers at Lewis Katz School of Medicine at Temple University shows that, in mice, this issue can reduced. Reintroducing LIN28 into stem cells obtained from adult heart tissue. LIN28 is a protein that normally expressed in growing heart. “LIN28 is very active in the developing heart, but not in the adult heart,” says, Moshin Khan, Assistant Professor of Cardiovascular Sciences at the Cardiovascular Research Center at the Lewis Katz School of Medicine. “We found that when we expressed LIN28 in cardiac stem cells from adult heart tissue, the adult cells were reprogrammed to have metabolic aspect of young, developing heart cells. The process was essentially like reverse aging.”
The fetal heart can function in less oxygen. After birth, this low oxygen tolerance disappear. However, heart becomes very sensitive to low oxygen, by adulthood. It is shown that changes in cellular metabolism are the main reason for this shift. Therefore, fate of stem cells after transplantation is control by these metabolic differences in heart as shown by recent studies.
In the new study, Dr Khan and team are working to find whether metabolic regulators expressed in developing heart could impart some kind of metabolic flexibility to cardiac tissue-derived stem-like cells (CTSCs).CTSCs are present in both children and adult heart tissue but LIN28 only express in developing heart. Whereas in adult heart tissue, CTSCs have self-renewal ability and are normally dormant.
Reintroducing LIN28 in adult mouse
The team started by reintroducing LIN28 expression in adult mouse CTSCs in vitro. Then they study the effects on signaling pathways involved in growth, cellular metabolism and self-renewal. They found that LIN28 expression induce a strong regenerative response, modifying CTSCs to increase growth and survival response to oxidative stress. Researchers related these changes to the Let7/PDK1 signaling pathway (regulated aerobic metabolism in cells). Hence, transplanting LIN28-expressing CTSCs in mice that had a heart attack showed great improvement in heart function and structure. These effects were considered to be the same pathways identified in the in vitro assessment.
“LIN28 modified energy production in CTSCs, leading to the secretion of many factors that are helpful for heart cell survival,” Dr. Khan explained. “Overall, the cells took on a more youthful phenotype.”
Future aspects in using Stem-cell based therapies
Dr. Khan’s future plan is to use the new discovery into larger animal model. Also to find out if LIN28 can improve the human-derived cardiac stem cells. “These studies could have important indication for how we use stem cell therapy for heart disease in humans,” he said.