Impact of Reactive Oxygen and Reactive Nitrogen Species for Stem Cell Mobilization, Function and Cardiovascular Differentiation

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Reactive oxygen species (ROS), i.e. substances like hydrogen peroxide (H2O2), the superoxide anion (O2-) or the highly reactive hydroxyl ion (HO-) as well as reactive nitrogen species (RNS) with nitric oxide (NO) as its most important member are ideally suited to serve as signaling molecules since they are locally generated, are highly and rapidly diffusible and can be neutralized by a bulk of anti-oxidative agents organized in the cellular anti-oxidative defense system. So far the signaling pathways regulating organ-specific differentiation of stem cells are largely unknown. Differentiation processes of stem cells embedded in tissues and organs are tightly regulated by the cellular microenvironment which is critically determined by the availability of nutrients and oxygen as well as by the balance of ROS and NO generation. Already during early embryogenesis NADPH oxidases and NO synthases are expressed in the growing embryo, suggesting that gradients of ROS and NO may exist in the developing organs and may be involved in proper functioning of commitment programs. During pathophysiological insults, e.g. during hypertension, atherosclerosis and cardiac infarction high levels of ROS and NO are generated, thus creating an inflammatory microenvironment which on one side contributes to cell damage, apoptosis and remodeling, however, on the other side may activate repair processes that involve recruitment and differentiation of stem cells of the cardiovascular cell lineage. During recent years emerging evidence suggests that ROS and RNS are involved in cardiovascular differentiation of embryonic (ES) and adult stem cells. Comparable effects may occur during differentiation processes of resident cardiac stem cells. A pivotal role for NADPH oxidases and NO synthases in cardiomyogenesis and vasculogenesis of ES cells has been recently outlined. In this chapter the current knowledge on activation, recruitment and differentiation of different cardiovascular stem cell populations by ROS and NO and the involved signal transduction cascade is reviewed. Furthermore the specific microenvironmental requirements for proper stem cell engraftment and maintenance are outlined.