Mesoangioblasts from ventricular vessels can differentiate in vitro into cardiac myocytes with sinoatrial-like properties.
Cardiac mesoangioblasts (MABs) are a class of vessel-associated clonogenic, self-renewing progenitor cells, recently identified in the post-natal murine heart and committed to cardiac differentiation. Cardiomyocytes generated during cardiogenesis from progenitor cells acquire several distinct phenotypes, corresponding to different functional properties in diverse structures of the adult heart. Given the special functional relevance to rhythm generation and rate control of sinoatrial cells, and in view of their prospective use in therapeutical applications, we sought to determine if, and to what extent, cardiac mesoangioblasts could also differentiate into myocytes with properties typical of mature pacemaker myocytes. We report here that a subpopulation of cardiac mesoangioblasts, induced to differentiate in vitro into cardiomyocytes, do acquire a phenotype with specific mature pacemaker myocytes properties. These include expression of the HCN4 isoform of pacemaker ("funny", f-) channels and connexin 45 (Cx45), as well as reduced expression of inwardly-rectifying potassium channels. Furthermore, MAB-derived myocytes form agglomerates of pacing cells displaying stable rhythmic activity, and as in native cardiac pacemaker cells, f-channel modulation by autonomic transmitters contributes to control of spontaneous rate in differentiated mesoangioblasts. These data represent the first evidence for in vitro generation of pacemaker-like myocytes from proliferating non-embryonic stem/progenitor cells.
Barbuti
Andrea
A
Department of Biomolecular Sciences and Biotechnology, The PaceLab, University of Milano, via Celoria 26, 20133 Milan, Italy. andrea.barbuti@unimi.it
Galvez
Beatriz G
BG
Crespi
Alessia
A
Scavone
Angela
A
Baruscotti
Mirko
M
Brioschi
Chiara
C
Cossu
Giulio
G
DiFrancesco
Dario
D
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology*; D002454:Cell Differentiation; D002999:Clone Cells; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D015415:Biomarkers; D054815:Cyclic Nucleotide-Gated Cation Channels; D050993:GATA6 Transcription Factor; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta; D011950:Receptors, Cholinergic