Cardiac fibroblast proliferation rates and collagen expression mature early and are unaltered with advancing age.

Anela Tosevska,Feiyang Ma,Arjun Deb,Rimao Wu,Colin Farrell,Matteo Pellegrini

doi:10.1172/jci.insight.140628

Anela Tosevska, Feiyang Ma + Show 4 more

Open Access

https://doi.org/10.1172/jci.insight.140628

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Journal: JCI insight	Publication Date: Dec 17, 2020
Citations: 15	License type: CC BY 4.0

Affiliation: University of California, Los Angeles

Abstract

Cardiac fibrosis is a pathophysiologic hallmark of the aging heart, but little is known about how fibroblast proliferation and transcriptional programs change throughout the life span of the organism. Using EdU pulse labeling, we demonstrated that more than 50% of cardiac fibroblasts were actively proliferating in the first day of postnatal life. However, by 4 weeks, only 10% of cardiac fibroblasts were proliferating. By early adulthood, the fraction of proliferating cardiac fibroblasts further decreased to approximately 2%, where it remained throughout the rest of the organism’s life. We observed that maximal changes in cardiac fibroblast transcriptional programs and, in particular, collagen and ECM gene expression both in the heart and cardiac fibroblast were maximal in the newly born and juvenile animal and decreased with organismal aging. Examination of DNA methylation changes both in the heart and in cardiac fibroblasts did not demonstrate significant changes in differentially methylated regions between young and old mice. Our observations demonstrate that cardiac fibroblasts attain a stable proliferation rate and transcriptional program early in the life span of the organism and suggest that phenotypic changes in the aging heart are not directly attributable to changes in proliferation rate or altered collagen expression in cardiac fibroblasts.

Highlights

The mammalian cardiac muscle cell is highly proliferative within the first few days of birth [1] but subsequently undergoes cell cycle arrest [2], and the myocyte undergoes minimal turnover for the rest of the life of the organism [3]
These observations suggest the highest rates of cardiac fibroblast proliferation are observed in the immediate postnatal period and that the proliferation rate rapidly declines by the early juvenile period (4 weeks) and significantly declines further to a stable and low level of cardiac fibroblast proliferation by early adulthood (14 weeks), remaining similar with advancing organismal age
Our data show the dynamics of fibroblast proliferation and transcriptional programs from early postnatal life to advanced age

Summary

Introduction

The mammalian cardiac muscle cell is highly proliferative within the first few days of birth [1] but subsequently undergoes cell cycle arrest [2], and the myocyte undergoes minimal turnover for the rest of the life of the organism [3]. Cardiac fibroblasts reside in an interstitial position between cardiomyocytes and are the principal cells that secrete extracellular matrix (ECM) [5] They exist in a quiescent state [6] in the uninjured heart; it is not clear whether fibroblasts exhibit an age-dependent increase in proliferation rate or increase in ECM gene expression that potentially contributes to age-related cardiac fibrosis. We determined cardiac fibroblast proliferation rates in hearts of mice at different ages by measuring markers of proliferation or by pulse labeling of animals with 5-ethynyl-2′-deoxyuridine (EdU) Using these corroborative methodologies, we observed that the highest rates of cardiac fibroblast proliferation were in the immediate postnatal period, with subsequent decline in the rates of proliferation across early juvenile and early adulthood periods.

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