Abstract
Cardiac interstitial cells (CICs) perform essential roles in myocardial biology through preservation of homeostasis as well as response to injury or stress. Studies of murine CIC biology reveal remarkable plasticity in terms of transcriptional reprogramming and ploidy state with important implications for function. Despite over a decade of characterization and in vivo utilization of adult c‐Kit+ CIC (cCIC), adaptability and functional responses upon delivery to adult mammalian hearts remain poorly understood. Limitations of characterizing cCIC biology following in vitro expansion and adoptive transfer into the adult heart were circumvented by delivery of the donated cells into early cardiogenic environments of embryonic, fetal, and early postnatal developing hearts. These three developmental stages were permissive for retention and persistence, enabling phenotypic evaluation of in vitro expanded cCICs after delivery as well as tissue response following introduction to the host environment. Embryonic blastocyst environment prompted cCIC integration into trophectoderm as well as persistence in amniochorionic membrane. Delivery to fetal myocardium yielded cCIC perivascular localization with fibroblast‐like phenotype, similar to cCICs introduced to postnatal P3 heart with persistent cell cycle activity for up to 4 weeks. Fibroblast‐like phenotype of exogenously transferred cCICs in fetal and postnatal cardiogenic environments is consistent with inability to contribute directly toward cardiogenesis and lack of functional integration with host myocardium. In contrast, cCICs incorporation into extra‐embryonic membranes is consistent with fate of polyploid cells in blastocysts. These findings provide insight into cCIC biology, their inherent predisposition toward fibroblast fates in cardiogenic environments, and remarkable participation in extra‐embryonic tissue formation.
Highlights
Myocardial homeostasis is maintained by dynamic interaction on multiple levels between cardiomyocytes and the cardiac interstitial cell (CIC) population
CCICs incorporation into extra-embryonic 22 membranes is consistent with fate of polyploid cells in blastocysts. These findings provide 23 insight into CIC subpopulation enriched for c-Kit+ expression (cCIC) biology, their inherent predisposition toward fibroblast fates in cardiogenic environments, and remarkable participation in extra-embryonic tissue formation
Studies of CIC biology often rely upon assessments performed using populations expanded by in vitro cell culture for various reasons of sample yield, manipulability, and simplification compared to challenges of the myocardial milieu in vivo [7,8,9,10,11]
Summary
Myocardial homeostasis is maintained by dynamic interaction on multiple levels between cardiomyocytes and the cardiac interstitial cell (CIC) population. A plethora of selected subpopulations of in vitro expanded CICs have been intensively studied for cardioprotective and reparative potential upon reintroduction into pathologically injured myocardium for over a decade [10,15,16], but consequences of cell culture environment upon CIC properties in terms of reshaping population characteristics or individual cellular functional capabilities remains relatively unstudied and poorly understood Such cultures involve two dimensional (2D) monolayer growth and serial passaging to obtain sufficient numbers of cells for treatments [17,18,19,20]. Despite irrefutable evidence of alterations following in vitro expansion of primary CIC isolates, there are essentially no studies to document the extent of such changes as permanent or transient and whether CICs undergo another round of phenotypic and functional adaptation following reintroduction to their native environment of in vivo myocardium
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