Stem Cell Treatment for Heart Attacks: Timing is Everything

Discussion of O'Blenes et al. Ann Thorac Surg. 2010 Mar 5th; 89(3):829-35

Skeletal myoblasts are a type of muscle-specific stem cell that have been used previously in several clinical trials, particularly for heart failure and post-heart attack patients.  Advantages of this type of stem cell include the fact that they are from adult sources (no risk of cancer), they are already committed to becoming muscle cells, and they can easily be grown in the laboratory.  Disadvantages include the possibility of arrhythmias, as well as lack of efficacy in several systems. Additionally, unlike mesenchymal stem cells, which can be used as "universal donors" because of their anti-inflammatory effects, skeletal myoblasts have to either be used from the same patient (autologous), or co-administered with immune suppression to prevent their rejection.

In a recent publication (O'Blenes et al. Engraftment is optimal when myoblasts are transplanted early: the role of hepatocyte growth factor. Ann Thorac Surg. 2010 Mar;89(3):829-35) Canadian researchers at Dalhousie University sought to determine whether an optimum time exists for myoblast administration after cardiac injury. 

Using rats, the scientists cut off circulation to the coronary artery to mimic a heart attack by ligation using microsurgery.  Myoblasts where implanted at the time of ligation or 5 weeks after the infarct.  Much higher engraftment of the cells was observed in animals that received the cells immediately after the infarct.  Additionally, the hearts that received myoblasts earlier seemed to have less damage.  This prompted the scientists to ask the question; "why would delayed administration result in less homing and retention?"

Previously we at Cellmedicine discussed the biological observation that after a heart attack the injured heart muscle generates chemicals that attract the body's own stem cells.  One of these chemicals is VEGF, which was discussed in this video http://www.youtube.com/watch?v=NqEggEYilh0. Another chemical made by injured heart tissue is hepatocyte growth factor (HGF).  Both of these proteins are made when cells "sense" reduced oxygen, as well as various alterations in their environment.  In the current study it was found that levels of HGF are substantially elevated after the infarct and subsequently diminish by the 5th week.  The investigators found that HGF stimulated proliferation and activity of the myoblasts, and therefore believed that the decline in HGF may be one of the reasons for the decreased efficacy with time. 

This could be a possible explanation for their results, however, numerous factors may also be important to consider.  For example, it is known in various situations of injury that as scar tissue forms, components of the scar tissue inhibit regeneration.  Stem cells such as bone marrow mesenchymal cells contain matrix metalloproteases that actively can "dig through" scar tissue and support regeneration.  Myoblasts do not express such enzymes, and additionally do not have the same homing ability to injured tissue.

The study would have substantially made more of a strong case for the importance of HGF in stem cell activity if they used blocking antibodies or knock-out mice specific for this gene.  Such a study would have conclusively demonstrated the importance of HGF in this situation by demonstrating less stem cell homing in its absence. 

One interesting point that is made is the possibility of administering HGF into the myocardium of patients so as to enhance stem cell homing.  Indeed, some companies such as Bioheart are already using such an approach, see link http://www.bioheartinc.com/prod-myocellsdf1.html.