Do Stem Cells from Bone Outdo Those from the Heart in Regenerating Cardiac Tissue?


Scientists at Tulane University in New Orleans, La. (US) have completed a study that suggests that stem cells derived from cortical, or compact bone do a better job of regenerating heart tissue than do the heart’s own stem cells.

The study, led by Steven R. Houser, Ph.D., FAHA, director of Tulane’s School of Medicine’s Cardiovascular Research Center (CVRC), could potentially lead to an “off the rack” source of stem cells for regenerating cardiac tissue following a heart attack.

Cortical bone stem cells (CBSCs) are considered some of the most pluripotent cells in the adult body. These cells are naïve and ready to differentiate into just about any cell type. However, even though CBSCs and similar pluripotent stem cells retain the ability to develop into any cell type required by the body, they have the potential to wander off course and land in unintended tissues. Cardiac stem cells, on the other hand, are more likely to stay in their resident tissue.

Bone cross-section

To determine how CBSCs might behave in the heart, Houser’s team, led by Temple graduate student Jason Duran, collected the cells from mouse tibias (shin bones), expanded them in the lab and then injected them into back the mice after they had undergone a heart attack.

The cells triggered the growth of new blood vessels in the injured tissue and six weeks after injection had differentiated into heart muscle cells. While generally smaller than native heart cells, the new cells had the same functional capabilities and overall improved survival and heart function.

Similar improvements were not observed in mice treated with cardiac stem cells, nor did those cells show evidence of differentiation.

“What we did generates as many questions as it does answers,” Dr. Houser said. “Cell therapy attempts to repopulate the heart with new heart cells. But which cells should be used, and when they should be put into the heart are among many unanswered questions.”

The next step will be to test the cells in larger animal models. The current study was published in the Aug. 16 issue of Circulation Research.

Remote Ischemic Conditioning Enhances Stem Cell Retention in the Heart


Stem cell administration to the heart after a heart attack is a difficult venture. Direct injection into the heart muscle is definitely the most sure-fire way to get stem cells into the heart tissue. However, direct injection requires that the physician crack the patient’s chest (thoracotomy), which is exquisitely unpleasant for the patient. Alternatively, there are devices that an deliver stem cell injections into the heart through the large veins in the legs, but these procedures require special equipment and lots of skills that your average cardiologist does not have. Another way is to administer stem cells through angioplasty. Using the same procedure as stent implantation, a delivery device is replaced at the site of heart damage through over-the-wire angioplasty technology, and the stem cells are delivered slowly and gradually through the coronary blood vessels. This does not require fancy equipment, and your average cardiologist could perform this technique pretty easily.

Problems exist with both procedures. Direct injection places cells and fluid into the heart wall and there is a risk of rupture. Likewise, with over-the-wire delivery of stem cells, there is the risk of clogging the coronary artery.

With both techniques, many stem cells end up in places other than the heart. In fact, the majority of the stem cells end up somewhere else – the lungs and liver mostly. Is there a better way?

Intravenous administration would be sweet, but that has been tried and the bottom line is that it bombed (Barbash et al., Circulation. 2003 19;108(7):863-8; Freyman et al., Eur Heart J. 2006 May;27(9):1114-22).

Well, some very enterprising scientists from China had an idea to get the intravenously administered stem cells to go to the heart and stay there. Bone marrow stem cells respond to a molecule called SDF1alpha (stromal cell derived factor-1alpha). On their cell surfaces, bone marrow cells have a receptor called CXCR4 which binds the SDF1alpha and bone marrow cells move towards higher and higher concentrations of SDF1alpha. Therefore, can you get the heart to make more SDF1alpha?

Sure. You can genetically engineer it to make more SDF1alpha. If you do that, the stem cells will pour out of the bone marrow and go to the heart and help fix it (Sundararaman S et al., Gene Ther. 2011 18(9):867-73). However, is there another way to get more SDF1alpha in the heart?

Yes there is. Let me introduce Remote Ischemic Conditioning or RIC. RIC increases the protection against injury that results from loss of blood flow to an organ. The way RIC works is that the blood supply to another organ is clamped so that this other organ is deprived of oxygen long enough to sound the alarm, but not long enough to do it serious damage. This deprivation of oxygen induces a flash of SDF1alpha production, which brings stem cells from bone marrow to the bloodstream and to the damaged organ.

Qin Jiang and colleagues from the Peking Union Medical College in Beijing, China used RIC in animals that had undergone a heart attack to determine if RIC could recruit more stem cells to the heart. Also, they administered bone marrow stem cells intravenously to see if RIC increased stem cell retention in the heart.

Jiang and others broke their laboratory rats into three groups (it gets a little complicated).

The first group was given heart attacks and then split into two subgroups. One subgroup received RIC and the second subgroup received surgery but no RIC.

The second group was given a heart attack and then split into six subgroups. Once subgroup was given RIC and intravenous bone marrow mesenchymal stem cells. the second received bone marrow mesenchymal stem cells by no RIC, only the incision, the third subgroup only received intravenous mesenchymal stem cells, the fourth group received RIC and intravenous saline, the fifth subgroup received no RIC, only an incision and intravenous saline, and the sixth subgroup received only intravenous saline.

The third group was given heart attacks and then split into two groups, one of which received RIC, intravenous mesenchymal stem cells and intravenous antibodies against CXCR4, and the other of which received RIC, mesenchymal stem cells and an antibody against nothing in particular.

The results showed that RIC GREATLY increased the amount of SDF1alpha in the heart. There was simply no getting around this. At 1 hour after RIC, SDF1alpha and VEGF (vascular endothelial growth factor) levels were up, but these levels decreased by 3 hours and back to normal by 6 hours after RIC.

Did these increased SDF1alpha levels increase stem cell retention? Oh yes!! The RIC-treated rats had almost twice the number of stem cells in their hearts than the animals that did not have RIC. Did this make a functional difference? Again, yes! The RIC-treated animals had hearts that functioned more normally (relatively speaking) than hearts from the non-RIC-treated animals.

The third experiment was even more informative, since the co-administration of the CXCR4 antibody abrogated the response induced by RIC. This demonstrates that effects of RIC are mediated by the SDF1alpha/CXCR4 axis and blocking this signaling axis prevented any benefits from RIC.

This paper is short, but very informative. It suggests that a relatively simple procedure like RIC could potentially improve the clinical efficacy of stem cell treatments. If this can be shown to work in larger animals, then clinical trials might be warranted. In fact clinical trials are presently underway in which SDF1alpha is being engineered into the heart to treat heart attack patients (see Hajjar RJ, Hulot JS. Circ Res. 2013 Mar 1;112(5):746-7).