Cardiac fibroblast diversity in health and disease

doi:10.1016/j.matbio.2020.05.003

Matrix Biology

Volumes 91–92, September 2020, Pages 75-91

https://doi.org/10.1016/j.matbio.2020.05.003 Get rights and content

Highlights

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Fibroblasts are transcriptionally, functionally and spatially heterogeneous.
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Fibroblast diversity is due to anatomical/niche-related and cell autonomous factors.
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A fibroblast subset termed FAPs possesses progenitor-like properties.
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Pericytes are likely a distinct stromal cell type and not a fibroblast subtype.
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FAPs possess organ-specific transcriptional signatures and lineage biases.

Abstract

The cardiac stroma plays essential roles in health and following cardiac damage. The major player of the stroma with respect to extracellular matrix deposition, maintenance and remodeling is the poorly defined fibroblast. It has long been recognized that there is considerable variability to the fibroblast phenotype. With the advent of new, high throughput analytical methods our understanding and appreciation of this heterogeneity has grown dramatically. This review aims to explore the diversity of cardiac fibroblasts and highlights new insights into the diverse nature of these cells and their progenitors as revealed by single cell sequencing and fate mapping studies. We propose that at least in part the observed heterogeneity is related to the existence of a differentiation cascade within stromal cells. Beyond in-organ heterogeneity, we also discuss how the stromal response to damage differs between non-regenerating organs such as the heart and regenerating organs such as skeletal muscle. In exploring possible causes for these differences, we outline that although fibrogenic cells from different organs overlap in many properties, they still possess organ-specific transcriptional signatures and differentiation biases that make them functionally distinct.

Introduction

The cardiac stroma plays key roles in homeostasis and during injury-induced remodeling. In the aftermath of myocardial infarction, a fibrogenic program is activated that eventually leads to the replacement of lost cardiac muscle with a rigid fibrous tissue [1]. Cardiac fibroblasts, loosely defined as plastic adherent stromal cells that secrete type I collagen and maintain the connective tissue, are the major contributors to the fibrogenic response in the heart [2].

Whether cardiac fibroblasts are phenotypically and functionally homogenous or whether they encompass different subsets with unique features and functions has been the subject of much study and controversy in the recent past [3,4]. With the advent of powerful tools enabling single cell biology, the nature and defining characteristics of the cells comprising our tissue is finally being defined not just through a few markers, but by taking a wholistic look at transcriptional programs. Through these approaches, it is apparent that fibroblasts are not only transcriptionally diverse, but also functionally, epigenetically and spatially heterogeneous. The precise extent of such heterogeneity is dependent on the tissue under analysis, with barrier organs such as skin containing multiple subsets of different function and cellular origin, and sterile organs such as muscles limited to cellular intermediates belonging to a single lineage [5,6].

Section snippets

Markers of cardiac fibroblasts: a source of confusion?

As shown in Table 1, many markers have been proposed to specifically label cardiac fibroblasts. However, most of them were shown to either be expressed on other cell types (non-specific) or only identify a subpopulation of fibroblasts. For example, fibroblast specific protein 1 (FSP1, also known as S100A4), is expressed on monocytes and smooth muscle cells; discoidin domain receptor 2 (DDR2) is expressed on smooth muscle cells and endothelial cells; CD90 (gene name is Thy1) is expressed on

Fibroblast heterogeneity

The diversity of cardiac fibroblasts arises from a number of factors. In addition to “cell autonomous” heterogeneity, related to lineage diversity and cellular properties (such as progenitor-like properties), transcriptional profile, and functional state (such as activation versus quiescence), it is likely that a significant amount of differences is due to the diverse microenvironments these cells are exposed to as a result of being in different anatomical locations within the heart [10]. In

Stromal response to damage in regenerative vs non-regenerative tissues

Despite their close phenotypic similarity across tissues, the response of resident FAPs to injury in regenerative organs such as skeletal muscles is significantly different from that observed in non-regenerative organs such as the heart. In skeletal muscles, following acute injury, FAPs markedly proliferate and secrete trophic factors that promote the expansion and myogenic differentiation of satellite cells (skeletal muscle stem cells) into mature myocytes [34]. Upon successful regeneration,

Concluding remarks and future directions

In conclusion, the diversity of fibroblasts has been described since long ago [104]. It was believed that different anatomical locations imparted some specific characteristics on the fibroblasts that reside in them [105]. As science progressed, it became apparent that fibroblasts are heterogeneous not only between different organs, but also within the same organ. Different anatomical locations harbor fibroblasts with distinct functions and transcriptional profiles. The emergence of single cell

Declaration of Competing Interest

Authors have no competing interests to declare.

Acknowledgments

The authors would like to thank the Rossi lab members for their help in proofreading the article.

Funding

This work was supported by Canadian Institutes of Health Research (grant FDN-159908) and the Heart and Stroke Foundation of Canada (grant G-19-0026541) to F.M.V.R.

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View full text

Cardiac fibroblast diversity in health and disease

Highlights

Abstract

Introduction

Section snippets

Markers of cardiac fibroblasts: a source of confusion?

Fibroblast heterogeneity

Stromal response to damage in regenerative vs non-regenerative tissues

Concluding remarks and future directions

Declaration of Competing Interest

Acknowledgments

Funding

Biol. Blood Marrow Transpl.

JACC Basic Transl. Sci.

Matrix Biol

Int. J. Biochem. Cell Biol.

Am. J. Pathol.

Stem Cell Rep.

Cell Stem Cell

Cell Stem Cell

J. Mol. Cell. Cardiol.

Cell Stem Cell

Cytotherapy

Cell Stem Cell

Cell Rep.

Cell

J. Am. Coll. Cardiol.

Exp. Cell Res.

J. Investig. Dermatol.

Dev. Biol.

Am. J. Pathol.

Cell Stem Cell

J. Am. Coll. Cardiol.

Am. J. Pathol.

Cell Rep.

Cell Stem Cell

Exp. Hematol.

Cell Stem Cell

Biochim. Biophys. Acta – Mol. Basis Dis.

Stem Cell Rep.

Am. J. Hum. Genet.

Mech. Dev.

Mech. Dev.

J. Biol. Chem.

Matricellular proteins in cardiac adaptation and disease

Physiol. Rev.

Redefining the identity of cardiac fibroblasts

Nat. Rev. Cardiol.

On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools for single cell analysis

Eur. Cells Mater.

Defining skin fibroblastic cell types beyond CD90

Front. Cell Dev. Biol.

Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair

Science (80-.).

Defining the cardiac fibroblast

Circ. J.

Genetic lineage tracing defines myofibroblast origin and function in the injured heart

Nat. Commun.

Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences

Circulation

Valve interstitial cells: the key to understanding the pathophysiology of heart valve calcification

J. Am. Heart Assoc.

Tracking adventitial fibroblast contribution to disease: a review of current methods to identify resident fibroblasts

Arterioscler. Thromb. Vasc. Biol.

Lineage tracing and genetic ablation of ADAM12 + perivascular cells identify a major source of profibrotic cells during acute tissue injury

Nat. Med.

Identification of a lineage of multipotent hematopoietic progenitors

Development

Evidence for minimal cardiogenic potential of stem cell antigen 1-positive cells in the adult mouse heart

Circulation

PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium

Nat. Commun.

Genetic lineage tracing of Sca-1+ cells reveals endothelial but not myogenic contribution to the murine heart

Circulation

Cardiac Sca-1 + cells are not intrinsic stem cells for myocardial development, renewal, and repair

Circulation

Fibroblasts and mesenchymal stem cells: two sides of the same coin?

J. Cell. Physiol.

Cardiac Sca-1 ⁺ cells are not intrinsic stem cells for myocardial development, renewal, and repair