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About the Authors:
Satoshi Yamanaka
Affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland, United States of America
Ihor Zahanich
Affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland, United States of America
Robert P. Wersto
Affiliation: Resource Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America
Kenneth R. Boheler
* E-mail: [email protected]
Affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland, United States of America
Introduction
The regenerative capacity of adult mammalian heart is insufficient to restore cardiac function following serious injury. The theory of cardiac self-renewal has led to several lines of investigation to improve the clinical outcome of patients with damaged myocardium [1]–[3]. One research avenue involves use of autocrine or paracrine factors to limit cell death, modulate the migration or activities of inflammatory and/or cardiomyogenic cells, and improve blood flow. This approach may reduce inflammation, limit scar formation, improve vascularization and help preserve or restore function. In cases where damage has already occurred, cell transplantation has emerged as a reparative strategy, but the optimal source of cells remains to be defined. Derivatives of embryonic and adult stem or progenitor cells with cardiomyogenic potential have been proposed, but their propensity to generate multiple cell types and the inability to isolate primary cells without intervening cultivation has complicated their use [3]–[6]. Another option involves activation of cardiomyocyte (CM) or precursor cell proliferation [7], [8]. Although evidence for endogenous proliferation in adult heart exists, most cells are thought to be mitotically quiescent and activation is insufficient for repair [9]–[11]. Considerable effort has therefore been invested in the study of CM cell cycle regulation, but with limited success.
Because no proliferating cell line sufficiently close to normal cardiac muscle cells has ever been available, attempts to generate proliferating CM to study cell cycle progression have generally relied on primary cultures and expression of transforming oncogenes, the utility of which is limited by their transformed phenotype. Investigators have also employed late fetal and neonatal (and some adult) rat CM after infection with recombinant adenoviruses to alter principal cell cycle regulators [7]; however, adenovirus gene transfer vectors can induce cell cycle dysregulation and inappropriate expression of cyclin proteins, which complicate the interpretation of published studies [12]. Transgenic mouse...