**3.1 Cardiac repair using CPC**

280 Congenital Heart Disease – Selected Aspects

Mouse studies have demonstrated homing of bone marrow-derived stem cells into the infarcted myocardium, suggesting a hematopoietic origin for c-Kit+ CPC. However, transdifferentiation of these cells into cardiomyocytes is controversial (Orlic et al., 2001; Murry et al., 2004; Bearzi et al., 2007). On the other hand, Tallini (Tallini et al., 2009) reported that c-Kit is expressed by immature cardiomyocytes as well as endothelial cells during development of mouse heart and that the populations rapidly expanded during the first 2 days of postnatal life. Their study compared the difference between the multipotency potential of CPC derived from the neonatal heart and the adult injured heart. They concluded that the neonatal c-Kit+ cells showed an ability to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells. In contrast, they found that c-Kit+ cells in the adult injured mouse heart had no myogenic capacity. The co-expression of c-Kit and neuronal marker Nestin in neonatal CPC (Tallini et al., 2009) suggests a transitional status of NCC in postnatal life and the potential for NCC contributing to cardiac repair and

The infant heart grows rapidly after birth. The pulmonary valve annular diameter doubles in the first 7 years of life and plateaus by age 14 (Sairanen & Louhimo, 1992) while left ventricular volume doubles over approximately the first 10 years of life (Nielsen et al., 2010). Although cardiomyocytes increase in volume (hypertrophic growth), in part by cellular fusion into very large multinucleate myocytes, there is also an overall increase in cellularity (cell number) in the heart during this rapid expansion phase of heart growth. That the number of myocytes continues to increase after birth has only recently been demonstrated. For decades, it was taken as fact that cardiomyocytes were incapable of dividing postnatally,

One of the earliest reports of new cardiomyocytes appearing in the postnatal human heart was provided by studies of adult aortic stenosis patients, in which cells co-expressing cardiac and stem cell markers could be localized (Urbanek et al., 2003). Additionally, studies of transplanted adult donor hearts revealed the appearance of new cardiomyocytes in the donor heart by the presence of sex chromosomes opposite to that of the recipient host (Bayes-Genis et al., 2007). Highly compelling further evidence that new myocytes are added to the heart over time arises from carbon isotope data (Bergmann et al., 2009) showing that nearly 50% of myocytes are replaced over a lifetime. Studies of the hearts of dogs with advanced dilated cardiomyopathy performed by Leri (Leri et al., 2001) showed postnatal proliferation of cardiomyocytes, documented by the expression of cell proliferation marker Ki67 and telomerase. Telomerase activity is not only required for cardiac growth and survival but it also suppresses cardiomyocyte apoptosis (Oh & Schneider, 2002). We (Amir et al., 2008) also demonstrated that the neonatal human heart contains cardiomyocytes expressing Ki67. We also determined that the number of these proliferating myocytes

Work by a number of investigators has demonstrated that a population of multipotent cardiac lineage-determined cells (i.e., CPC) capable of further differentiation to all cardiac cell types is present in all hearts. Hence, continued cardiomyocyte renewal has slowly been gaining acceptance as both an important aspect of normal myocardial biology and a potential strategy to assist with repair of a diseased heart. The ability to expand the

if only because mitosis of a multinucleated cell is considered impossible.

declines nearly 6-fold in the first two months of life.

**2.4 Summary: CPC in the postnatal myocardium** 

remodeling (Drapeau et al., 2005).

**2.3 Postnatal heart growth** 

#### **3.1.1 Role of CPC in homeostatic repair and postsurgical healing**

If the heart can add new cells, then the question arises regarding why it doesn't always heal itself? The generally offered explanation for the fact that resident CPC are unable to naturally rescue a moderately infarcted adult heart is that the region of damaged tissue is too great for this mechanism to work rapidly enough to restore function. Although not widely recognized, "silent "repair by CPC has been observed (see section 3.2.1). It is probable that small lesions in the myocardium are actually self-repaired silently through expansion of the resident CPC population. Large ischemic lesions would be expected to also result in the loss of resident CPC in the infarcted region, further impairing self-repair. However, progress has recently been reported. Intra-myocardial injection of autologous bone marrow derived stem cells has been used in adults with chronic ischemic heart disease (i.e. not infarcted) to achieve functional recovery and reverse ventricular remodeling (Williams et al., 2011). Such reports of success strengthen the concept that endogenous stem cells can provide clinically significant benefits to heart disease patients of all ages.
