Myocardial Regeneration

(Chapter 1)

Understanding the basics:

In the past decade several attempts have been made to characterize and identify cells capable of differentiating into other lineages different form its organ of origin. Embryonic Stem cells (ESCs) and Bone marrow derived cells (BMCs) were extensively studied and striking advances have been made in utilizing the BMCs regenerative capacity for treating ischemic and nonischemic heart failures. However a lot of controversy surrounds the differentiative capacity of BMCs into cardiac lineages. The presence of a different stem cell compartment in the heart for regeneration of myocardial tissue after infarction has received recognition. Hematopoietic Stem cells (HSCs) with their transdifferentiation capabilities have been identified as the novel form of cell based therapy for regenerating damaged organs. Complete structural and functional recovery of the damaged organ is one of the basic aims of regenerative medicine. Scar formation during recovery from injury is vital for prevent a cascade of uncontrolled lethal events however the scar is biochemically and functionally dissimilar to the original tissue thereby hindering the performance of the organ in question.

Tissue repair in embryos is rapid and virtually scar free. Presence of hyaluronic acid and fibronectin in amniotic fluid has been linked to the interference in scar formation. Moreover less number of inflammatory cells accumulate at the site of Injury (attenuated response) and presence of growth factors such as transforming growth factor-β (TGF-β) isoforms which are not present in adults are deemed responsible for this. There have been studies where adult wounds in rats and mice when exposed to similar profile of cytokines which are present in embryo exhibit more efficient repair with reduction in scar formation.

Exogenous progenitor cells and myocardial repair:

During embryonic and post natal development there is increase in cardiac mass which reflects the delicate balance between formation of new myocytes and deletition of unwanted cells. Growth in myocyte right from birth is responsible for the adult heart phenotype. Cell homeostasis and optimal pump performance are often maintained by intrinsic growth factors however increased pressure or stress results in myocyte hypertrophy, apoptosis and necrosis which constitutes as infarction. Ischemic injury often results in decrease in number of myocytes and scarring. Numbers of experiments aimed at replacement of dead tissue with feasible cells have been developed to overcome this obstacle. Different types of cells were employed for experimentation of myocardial regeneration, these include skeletal myoblasts, embryonic myoblasts right upto bone marrow c-kit positive and negative progenitor cells. Mostly the implanted cells formed a passive graft and successfully decreased the stiffness around the scarred area and enhanced cardiac function. The possibility of a paracrine effect on resident cardiac stem cells by the implanted cells activating myocardial regeneration has been postulated however there has been little success in identification of the most appropriate form of cell therapy for myocardial repair.

Reference (Leri, A. et.al., Cardiac Stem Cells and Mechanisms of Myocardial Regeneration)