Appendix M. 
373 
large, prospective series, questions that remain to be addressed 
include whether the skeletal myoblasts can make meaningful 
electromechamcal connections to the surrounding endogenous 
cardiomyocytes through gap junctions, whether the cellular mass 
will contract in concert, and whether electrical impulses vshll be 
transmitted to the myoblast tissue without inducing significant 
tachyarrhythmias . 
Poor Survival Of Cells Transplanted Into Damaged Myocardium 
After Ex Vivo Culture. A major limitation to successful cellular 
therapy in animal models of myocardial damage has been the 
inability of the introduced donor cells to survive in their host 
environment, whether such transplants have been congenic 
(analogous to the autologous scenario in humans) or allogeneic. It 
has become clear that a major impediment to survival of the 
implanted cells is the alteration of their immunogenic character by 
prolonged ex vivo culture conditions. For example, whereas 
myocardial implantation of skeletal muscle in the absence of tissue 
culture does not induce any adverse immune response and results in 
grafts showing excellent survival for up to a year, injection of 
cultured isolated (congenic) myoblasts results in a massive and rapid 
necrosis of donor myoblasts, wnth over 90% dead within the first hour 
after injection This rapid myoblast death appears to be 
mediated by host natural killer (NK) cells “ which respond to 
immunogenic antigens on the transplanted myoblasts altered by 
exposure to tissue culture conditions It seems likely that a similar 
mechanism of host NK cell-mediated rejection v\hll apply also to 
transplanted ES-derived, cultured cardiomyocytes since massive 
death of injected donor cells is recognized as a major problem with 
transplanted cardiomyocytes, especially in the inflammatory 
conditions that follow infarction In this regard, the report that 
cultured mesenchymal stem cells obtained from adult human bone 
marrow are not rejected on transfer to other species is intriguing 
needs confirmation in humans, and requires detailed investigation 
into possible tolerogenic mechanisms. 
Concomitant Induction Of Vascular Structures Augments Survived 
and Function Of Cardiomyocyte Precursors. An additional 
explanation for the poor survival of transplanted cardiomyocytes or 
skeletal myoblasts may be that viability and prolonged function of 
transplanted cells requires an augmented vascular supply. Whereas 
many transplanted cardiomyocytes die by apoptosis, cultured 
cardiomyocytes that incorporate more vascular structures in vivo 
demonstrate significantly greater survival^. Moreover, in situations 
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