Human Placenta-Derived Multipotent Cells Modulate Cardiac Injury in Large and Small Animal Models

Placental-derived multipotent cells or PDMCs have been isolated from human term placental tissues. PDMCs have the ability to differentiate into neurons, bone, fat, and liver. Can cells like these help heal a damaged heart?

Men-Luh Yen and his colleagues from the National Taiwan University Hospital, Taipei, Taiwan, have recently published a large study of PDMCs that have examined the characteristics of these cells in culture and in small and large animals.

In culture, when PDMCs are grown with mouse heart muscle cells for eight days that differentiate into cells that look a lot like heart muscle cells.  These cells express the heart-specific gene alpha-sarcomeric actinin.  This is not evidence that PDMCs can differentiate into heart muscle cells, but it is evidence that they differentiate into heart muscle-like cells.  It is possible that these cells might be able to completely differentiate into heart muscle cells with the right signals.

When the culture medium from PDMCs are used to grow human umbilical vein endothelial cells, the human umbilical vein endothelial cells formed blood vessel-like tubes.  This indicates that PDMCs secrete a host of growth factors that induce the formation of blood vessels.  When Yen and his group examined the genes expressed by cultured PDMCs, they discovered that they expressed several growth factors known to induce blood vessel formation, such as hepatocyte growth factor (HGF), interleukin-8 (IL-8), and growth-regulated oncogene (GRO).  When these growth factors were given to cultured umbilical vein endothelial cells, they formed blood vessel-like tubes.  Thus HGF, GRO and IL-6 promote the formation of blood vessels.

When PDMCs were used to treat the heart of mice that had suffered a heart attack.  This part of the paper is less satisfying because many of their mice died as a result of this procedure (5 or 18).  However, the PDMS-treated mice did show a steady improvement in their ejection fractions (percentage of blood volume ejected from the heart) compared to mice that were only injected with culture medium.  These PDMC-injected mice also had extensive capillary beds in their heart tissue, suggesting that the increased heart function was due to the induction of new blood vessels.  In all honesty, this section of the paper should have had better controls and more animals should have been tested.  A sham group should have been included with an untreated group as well.

To extend their experiments in living animals, Yen’s group used a similar experimental strategy in Lanyu minipigs.  Here again, a lack of proper controls and large numbers of dead animals (5 of 17) diminish the clarity of the data.  The PDMC-treated minipigs showed a significant increase in ejection fraction (53.8 plus or minus 4.4 percent in the PDMC-treated minipigs vs. 39.2 plus or minus 2.3 percent in the culture medium-treated minipigs).  Also the blood vessel density in the hearts of the PDMC-treated pigs was over three times that of the other group.  Cell death studies showed that the hearts of the PDMC-treated minipigs that half that of the non-stem cell-treated minipigs.  This shows that PDMCs secrete molecules that promote cell survival.

Finally, Yen and others present what they think is evidence that the injected PDMCs in the hearts of the minipigs differentiated into heart muscle cells.  First of all, implanted PDMCs were observed eight weeks after they were injected.  There is little reason to suppose that these cells would have survived if they were not tightly associated with resident heart cells.  Secondly, these PDMCs expressed two heart-specific genes:  cardiac troponin T (cTNT), which is important for heart muscle contraction, and connexin 43, which is integral for forming gap junctions between heart muscle cells.  Gap junctions allow heart muscle cells to stay electrically connected with one another and allow them to contract as a single unit and these cells were expressing connexin 43 and were apparently integrated into the heart muscle.

I must say that I do not find this convincing, since the fusion of heart muscle cells and injected stem cells can account for such data.  Before I would believe that PDMCs can transdifferentiate into heart muscle cells, I would need to see compelling evidence that the connexin 43, cTNT, and human HLA-expressing cells also do not express minipig-specific genes.  Secondly, I would need to see PDMCs express the genes for the calcium-handling system that is unique to heart muscle cells.  The lack of express of these proteins is the single best reason to doubt that mesenchymal stem cells can transdifferentiate into heart muscle cells.  There is evidence that mesenchymal stem cells that stimulate endogenous heart stem cells to make new heart muscle, but little good evidence that mesenchymal stem cells can form mature, functional heart muscle cells.

All in all, the Yen paper shows some interesting data, even if some of it is not top quality.  Clear PDMCs are interesting cells that have a potential future in regenerative medicine.