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Sustained pacemaker function is a challenge in biological pacemaker engineering. Human cardiomyocyte progenitor cells (CMPCs) have exhibited extended survival in the heart after transplantation. We studied whether lentivirally transduced CMPCs that express the pacemaker current I_f (encoded by HCN4) can be used as functional gene delivery vehicle in biological pacing. Human CMPCs were isolated from fetal hearts using magnetic beads coated with Sca-1 antibody, cultured in nondifferentiating conditions, and transduced with a green fluorescent protein (GFP)- or HCN4-GFP-expressing lentivirus. A patch-clamp analysis showed a large hyperpolarization-activated, time-dependent inward current (−20 pA/pF at −140 mV, n = 14) with properties typical of I_f in HCN4-GFP-expressing CMPCs. Gap-junctional coupling between CMPCs and neonatal rat ventricular myocytes (NRVMs) was demonstrated by efficient dye transfer and changes in spontaneous beating activity. In organ explant cultures, the number of preparations showing spontaneous beating activity increased from 6.3% in CMPC/GFP-injected preparations to 68.2% in CMPC/HCN4-GFP-injected preparations (P < 0.05). Furthermore, in CMPC/HCN4-GFP-injected preparations, isoproterenol induced a significant reduction in cycle lengths from 648 ± 169 to 392 ± 71 ms (P < 0.05). In sum, CMPCs expressing HCN4-GFP functionally couple to NRVMs and induce physiologically controlled pacemaker activity and may therefore provide an attractive delivery platform for sustained pacemaker function. Full article

The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias observed after myocardial infarction. In other cardiac diseases, such as congenital heart disease, autonomic dysfunction may be related to disease outcome. This is also the case after heart transplantation, when the heart is denervated. Interest in the origin of the autonomic nerve system has renewed since the role of autonomic function in disease progression was recognized, and some plasticity in autonomic regeneration is evident. As with many pathological processes, autonomic dysfunction based on pathological innervation may be a partial recapitulation of the early development of innervation. As such, insight into the development of cardiac innervation and an understanding of the cellular background contributing to cardiac innervation during different phases of development is required. This review describes the development of the cANS and focuses on the cellular contributions, either directly by delivering cells or indirectly by secretion of necessary factors or cell-derivatives. Full article