Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Abstract

Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis‐related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis‐related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease—enabled through more accurate preclinical modeling—will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients.

Hyaluronic Acid Hydrogels with Phototunable Supramolecular Cross-Linking for Spatially Controlled Lymphatic Tube Formation

“…Mechanical cues are important in regulating the function of endothelial cells during vascular and lymphatic development. − Dynamic mechanical properties, such as the shear stress induced by fluid flow, have inspired the design of dynamic hydrogels for engineering vascular and lymphatic tissues. − ECM with softer mechanics has been shown to enhance lymphatic vessel formation by inducing a globin transcription factor binding protein 2 (GATA2) dependent transcriptional program . We previously showed a covalently cross-linked HA hydrogel with matrix stiffness priming lymphatic CLS formation directed by vascular endothelial growth factor-C (VEGF-C) .…”

Characterization of Photo-Crosslinked Methacrylated Type I Collagen as a Platform to Investigate Lymphatic Endothelial Cell Response

“…Recently, there has been increased focus on the relationship between tissues stiffness and lymphatic vessel response, primarily with lymphatic capillaries and LECs [6][7][8]. For our study, we focused on tissue stiffness levels that are found in fibrotic disease conditions, since tissue stiffening from excess ECM deposition and crosslinking are major features of fibrosis that alter the biophysical and biochemical microenvironments surrounding lymphatic vasculature.…”

“…In many of these healing and disease states, the tissue surrounding lymphatic vasculature undergoes dynamic biochemical (e.g., soluble factors) and biophysical (e.g., stiffness) changes that influence cell behavior [2][3][4][5]. One important biophysical change is increased tissue stiffening that is often associated with chronic fibrosis-a pathological wound healing condition marked by excess tissue deposition and scarring [6]. Increased tissue deposition and subsequent tissue densification also alters tissue transport properties, which changes the biochemical environment by altering how signaling molecules move through the tissue to reach cells.…”