MinireviewRegeneration in heart disease—Is ECM the key?
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Regeneration in heart disease
Evidence from rodent and human studies challenges the view of the heart as a terminally differentiated organ (Bergmann et al., 2009, Hsieh et al., 2007). The heart possesses regenerative capacity attributed to endogenous and exogenous progenitor cell populations (Liao et al., 2007) recently identified in adult myocardium. Intrinsically, this regenerative capacity is insufficient to prevent the progression toward heart failure following various insults. To address this limitation, a common
ECM changes in heart disease
Cardiomyocytes account for only one-third of the cell quantity in the adult mammalian heart (Zak, 1973). Fibroblasts are the largest population of non-myocytes, producing the intricate network of extracellular matrix (ECM) proteins providing orientation and anchorage to surrounding cardiomyocytes (Weber, 1989). The physiologic and pathologic importance of the ECM network is well studied. The primary components of the ventricular ECM network are Collagens I and III, among other structural
Cells feel their surroundings
Cells display methods to sense their surroundings and can react to perceived changes. This was first discovered through the observation that cell shape controls proliferation in cell cultures (Folkman and Moscona, 1978). Afterwards, ECM components were recognized to either interact directly with cells or to modulate growth factor stimulation (Hynes, 2009). Mechanical properties, such as stiffness, constitute a third factor by which the ECM controls cell function (Guilak et al., 2009, Tulloch et
ECM effects on cardiac development
Studying cardiac development can guide the understanding of influences of ECM composition and mechanical properties on stem/progenitor cells. During cardiac development, tissue stiffness changes (Young and Engler, 2011). Further, cell shape and arrangement vary—particularly during looping of the embryonic heart tube (Manasek et al., 1972)—coinciding with changes in ECM composition (Bowers and Baudino, 2010, Chan et al., 2010). When cells from embryonic cardiac fields are cultured on hydrogels
ECM effects on progenitor cells
Stem and progenitor cells in various tissues reside in specific niches (Moore and Lemischka, 2006). These niches are defined by cell–cell as well as cell–ECM interactions and are known to determine stem cell function and fate (Votteler et al., 2010). Similarly, progenitor cells in the heart reside in defined niches (Bearzi et al., 2007, Urbanek et al., 2006). Ckit + cardiac progenitor cells were found to express β1 integrin and are in close contact with laminin and surrounding cardiomyocytes (
Conclusions
ECM composition and mechanical properties play a significant role in cardiac development, and these factors are significantly altered during the pathogenesis of heart disease (Fig. 1). Little is known regarding the mechanical influence of ECM on progenitor cell fate, and the resultant effects of altered ECM composition on adult cardiac progenitor cells and cardiac regeneration potential remain to be determined, particularly in order to realize the potential of therapeutic regeneration. One key
Conflict of interest statement
The authors declare that there is no conflict of interest.
Acknowledgement
This work was supported by National Institutes of Health grants (HL086967, HL093148, and HL099073) and a research fellowship from the Sarnoff Cardiovascular Research Foundation (Ahmad F. Bayomy).
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