Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Abstract

Background: The sinoatrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. Methods: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. Results: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. Conclusions: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.

Trends in research on sick sinus syndrome: A bibliometric analysis from 2000 to 2022

“…Among which, Tbx 3 was not involved in the morphological development of the SAN but played an important role in regulating the function of the SAN ( 67 ). Tbx 18 gene was mainly involved in the development of the head of the SAN ( 68 ). ISL-1 was one of the molecular markers of undifferentiated cardiac histocytes/heart cells in the second cardiac region, which can promote cardiac development and differentiation ( 69 ).…”

Interaction of Pacemaker Cells and Fibroblasts in the SAN. Another Way of Setting the “Clocks”?

“…Otherwise, leading centers would be on the periphery. 10 Thus, in this new study, Chou et al 8 not only experimentally demonstrated for the first time that pacemaker activity of SAN is modulated by the fibroblasts present in the microenvironment but also reported the challenging theory that this effect is produced by constitutive metabolic reprogramming. The authors proposed that the integrin-dependent cell contact activates the PC p38 MAP (mitogen-activated protein) kinase, which stimulates the E2F1 transcription factor and promotes the expression of aldolase c (aldo c), a crucial enzyme in the process of glycolysis, enhancing aerobic glycolysis and the beating rate (Figure).…”

“…Chou et al 8 showed that interruption of fibroblast-PCs interaction or aldo c knockdown greatly reduced electrical activity. Clearly, the connection to the fibroblast and the subsequent activation of aldo c are important to modulate the DD.…”

“…Finally, the novel mechanistic insight provided by Chou et al 8 on the tight communication between the fibroblasts and PCs opens a whole set of interesting questions to be answered. Some of them are the following:…”

“…7 Unlike the role of fibroblasts in pathological fibrotic remodeling, little is known about the physiological interaction between fibroblasts and PCs in the SAN. In this issue of Circulation Research , Chou et al 8 demonstrated that fibroblasts can regulate rhythmicity by cellular-cellular interaction with PCs. The authors elegantly demonstrated that the relationship between both cell types is not a paracrine communication because the heartbeat modulation could not be reproduced when they performed a fibroblasts-PCs coculture separated by a porous membrane.…”