Mesenchymal stem cells from bone marrow, fat, and other tissues show remarkable abilities to induce healing of various damaged tissues. Several experiments in laboratory animals have established the ability of these cells to improve heart function after a heart attack, and these results have also been confirmed by many clinical trials that have transplanted bone marrow-derived mesenchymal stem cells into the hearts of human patients after a heart attack.
The difficulty with such treatments is that the transplanted mesenchymal stem cells (MSCs) find themselves in a hostile environment that tends to cause them to die. Several enterprising scientists have tried to mitigate this problem by pre-conditioning the MSCs or by genetically engineering them to survive in a tough milieu such as the infarcted heart. These experimented have resulted in greater MSC survival and better recovery of heart function after a heart attack. A recent clinical trial has also shown that ischemia-treated MSCs show increased ability to improve heart function after a heart attack.
Into this fray comes a very interesting paper in the journal Acta Biochimica et Biophysica Sina that uses the anti-cholesterol drug atorvastatin (Lipitor) to increase the survival of implanted MSCs from fat. In this paper, Anping Cai and Dongdan Zheng at the First Affiliated Hospital of Sun Yat-sen University in Guangzhou, China, in the laboratory of Weiyi Mai extracted rat MSCs from fat and then cultured them to convert them into heart muscle cells. This culture system involves co-culturing fat MSCs with heart muscle cells. Previous work has shown that when MSCs are co-cultured with MSCs, the MSCs tend to start expressing heart muscle-specific genes and even spread out and start of look and act like heart muscle cells. By using antibodies to heart muscle-specific proteins, Cai and Zheng and co-workers showed that most of the cultured MSCs had, in fact, converted to heart muscle cells. These cells also beat in culture, attached to other heart muscle cells and beat in synchrony with them.
Next, they took Sprague-Dawley rats and used surgical procedures to give these rats heart attacks. Fourteen days later, the rats were divided into five groups: 1) the first groups were operated on, but they were not given heart attacks (Sham operated); 2) a group to which one million heart muscle-like MSCs were transplanted into the damaged heart; 3) a group to which one million heart muscle-like MSCs were transplanted plus Lipitor (10 mg/kg/day) 4) a group to which Lipitor was injected into the heart; 5) a group to which Lipitor and MSCs that had not been differentiated into heart muscle cells was injected into the heart. The rats were kept for four weeks and then the animals were sacrificed and their hearts were examined.
The results are rather interesting. The hearts were examined for the degree of inflammation in them. Hearts that have experienced a heart attack are full of inflammatory cells and the damaging chemicals made by them. The animals that had been given Lipitor had substantially less inflammation in their hearts. Also, the MSCs that had been converted into heart muscle cells showed the greatest degree of survival (35%), but the undifferentiated MSCs showed the highest amount of heart muscle-specific gene expression.
When heart function was examined in the five groups, the sham group showed the highest heart function, but all four other groups showed large decrease in heart function after the heart attack (no surprise there). However, all the groups showed some improvement except for the group that was not give any Lipitor. The Lipitor-only group improved after two weeks, but these improvements disappeared after two more weeks. The two groups implanted with Lipitor and MSCs showed the best improvements. Of these two groups, the rats implanted with Lipitor and differentiated MSCs showed the most improvements in heart function. While they were not the same as the sham-operated rats, their functional parameters were reasonably close, which indicates that under the direction of the differentiated MSCs, the hearts of these rats had experienced generous healing.
Thus MSCs can survive and heal the hearts of heart attack patients, but in order to help them survive in the hostile environment of the infarcted heart, drugs like Lipitor can help them survive. Lipitor seems to do this by decreasing inflammation in the damaged heart, which allows the MSCs to work their healing magic in the heart.