The right ventricular fibroblast secretome drives cardiomyocyte dedifferentiation

Abstract

Rationale In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We’ve previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. Objective To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. Methods and results Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. Conclusions These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.

Dual Function of iPSC-Derived Pericyte-Like Cells in Vascularization and Fibrosis-Related Cardiac Tissue Remodeling In Vitro

“…Additional options could be the inhibition of myofibroblast differentiation, as has been shown in spinal cord injury, where the inhibition of PC proliferation and its contribution to ECM resulted in facilitated healing and reduced fibrosis [ 74 ]. Myofibroblast-secreted POSTN was also identified as an activator of cardiac dedifferentiation in pulmonary hypertension-induced heart failure [ 75 ], while the loss of POSTN function could lead to attenuated fibrosis.…”

Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

“…In association with increased RV and LV fibrosis in AAC-Kcnk3-mutated rats, we found an increase in Periostin expression. Periostin is known to modulate the transition of fibroblasts to myofibroblasts, collagen fibrillogenesis, ECM synthesis as well as the inflammatory response 31 Periostin-secreted from cardiac fibroblast drives cardiomyocyte dedifferentiation, contributing to RV dysfunction in experimental PH 32 . In our study increased Periostin in the 4 cardiac chambers could partly explain exaggerated peri-vascular inflammation and cardiac fibrosis.…”

Right versus left ventricular remodeling in heart failure due to chronic volume overload

“…The most upregulated protein in ACF ventricles was periostin (POSTN)—a non-structural component of ECM, marker of myofibroblasts, cells necessary for cardiac adaptive healing and fibrosis 36 . Periostin assists in deposition of fibronectin-rich ECM and collagen crosslinking 37 , cardiomyocyte dedifferentiation 38 and is extensively upregulated by TGFβ1, angiotensin II, infarction or hemodynamic overload, including VO 39 , 40 . VO-driven upregulation is almost twice in RV than in LV.…”