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Review
. 2023 Aug 14;11(8):2264.
doi: 10.3390/biomedicines11082264.

Understanding Fibroblast Heterogeneity in Form and Function

Jennifer B Parker  1   2 , Caleb Valencia  1 , Deena Akras  1 , Sarah E DiIorio  1   2 , Michelle F Griffin  1 , Michael T Longaker  1 , Derrick C Wan  1
Affiliations
Review

Understanding Fibroblast Heterogeneity in Form and Function

Jennifer B Parker et al. Biomedicines. .

Abstract

Historically believed to be a homogeneous cell type that is often overlooked, fibroblasts are more and more understood to be heterogeneous in nature. Though the mechanisms behind how fibroblasts participate in homeostasis and pathology are just beginning to be understood, these cells are believed to be highly dynamic and play key roles in fibrosis and remodeling. Focusing primarily on fibroblasts within the skin and during wound healing, we describe the field's current understanding of fibroblast heterogeneity in form and function. From differences due to embryonic origins to anatomical variations, we explore the diverse contributions that fibroblasts have in fibrosis and plasticity. Following this, we describe molecular techniques used in the field to provide deeper insights into subpopulations of fibroblasts and their varied roles in complex processes such as wound healing. Limitations to current work are also discussed, with a focus on future directions that investigators are recommended to take in order to gain a deeper understanding of fibroblast biology and to develop potential targets for translational applications in a clinical setting.

Keywords: dermis; fibroblast; fibrosis; heterogeneity; wound healing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Engrailed-1 positive fibroblasts are the key fibroblast subpopulation contributing to dermal scarring in the mouse dorsum. During injury, a subpopulation of fibroblasts, Engrailed-1 positive fibroblasts (EPFs) are the primary fibroblast contributing to skin scarring. Due to mechanical tension within the wound bed, Yes-Associated Protein (YAP) signaling activates Engrailed-1 and subsequent scar deposition. Inhibition of YAP signaling chemically via verteporfin or with the use of a genetic knock-out prevents activation of Engrailed-1, leading to reduced scar deposition and a regenerative phenotype. Figure taken with permission from “Converting fibroblastic fates leads to wound healing without scar” by Jiang and Rinkevich [43].
Figure 2
Figure 2
Pseudotime trajectory analysis as an example of computation tool to investigate fibroblast heterogeneity. Pseudotime trajectory analysis can be used to infer gene expression dynamics within a given group of cells. In this panel taken with permission from Mascharak et al. [10], differential gene expression between fibroblasts from control scars, from scars treated with an antifibrotic agent, and from unwounded skin, demonstrated a split into two major trajectories: fibrotic and regenerative.
Figure 3
Figure 3
Fibroblast heterogeneity across organ systems. Fibroblasts exhibit differences in gene expression and function based on organ system. Liver fibroblasts can be found alongside the portal tract, termed portal fibroblast. Myofibroblasts expressing alpha-Smooth Muscle Actin (α-SMA) and Collagen Type I (COL1A1) can be found in the scar. Portal fibroblasts can be found along the portal tract (top left). Upon injury to the heart, cardiac fibroblasts are activated and deposit excess extracellular matrix (ECM) that uniquely contains Cartilage oligomeric matrix protein (COMP) and thrombospondin 4, both of which confer strength to the new scar but result in a functionally deficient scar (top right). In the intestine, two broadly defined subpopulations of fibroblasts are found: CD81+ and Platelet-Derived Growth Factor Alpha (PDGFRa)lo, CD81−. CD81+ fibroblasts (red) can be found beneath the crypts, which play a role in intestinal renewal. PDGFRalo, CD81− fibroblasts reside within the lamina propria and contribute to the production of ECM and remodeling (bottom left). Within the skin, subpopulations of fibroblasts exist within different layers of the skin. Papillary fibroblasts (yellow) are FAP+ cells found in the papillary dermis and believed to contribute to hair growth regulation, piloerection control, and late-stage wound repair. Reticular fibroblasts (red) are CD90+ cells found in the reticular layer of the skin and participate in fibrillar ECM formation and contribute to the initial stages of wound repair (bottom right).
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