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.