Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

Abstract

The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering. Historically, work in this field has primarily focused on the delivery of large cytokines and growth factors, which can be costly to manufacture and difficult to deliver in a sustained manner. There has been a marked increase over the past decade in the pursuit of lipid mediators due to their wide range of effects over multiple cell types, low cost, and ease of scale-up. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two bioactive lysophospholipids (LPLs) that have gained attention for use as pharmacological agents in tissue engineering applications. While these lipids can have similar effects on cellular response, they possess distinct chemical backbones, mechanisms of synthesis and degradation, and signaling pathways using a discrete set of G-protein-coupled receptors (GPCRs). LPA and S1P predominantly act extracellularly on their GPCRs and can directly regulate cell survival, differentiation, cytokine secretion, proliferation, and migration-each of the important functions that must be considered in regenerative medicine. In addition to these potent physiological functions, these LPLs play pivotal roles in a number of pathophysiological processes. To capitalize on the promise of these molecules in tissue engineering, these lipids have been incorporated into biomaterials for in vivo delivery. Here, we survey the effects of LPA and S1P on both cellular-and tissue-level phenotypes, with an eye toward regulating stem/progenitor cell growth and differentiation. In particular, we examine work that has translational applications for cell-based tissue engineering strategies in promoting cell survival, bone and cartilage engineering, and therapeutic angiogenesis.

Translating GWAS Into the Flow-Regulated Modulation of Lipid Mediator Signaling

“…The bulk of LPA found in the circulation is generated by the action of autotaxin, a circulating lysophospholipase D enzyme secreted in large amounts by the liver and activated platelets, as well as from adipocytes. 12 This in itself is interesting because it may strengthen the link between platelet activation and increased fat mass with the accelerated development of cardiovascular disease. Thus, the findings by Wu et al 2 add support to studies implicating the autotaxin-lipid phosphate phosphatase pathway as a risk factor for coronary artery disease.…”

The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle

“…Sphingosine‐1‐phosphate (S1P) signaling via S1P receptors (S1PR) has been shown to modulate cardiovascular homeostasis, inflammation, and other important physiological functions . The sphingosine analog FTY720 (fingolimod) has been approved for the immunomodulatory treatment of multiple sclerosis.…”

Alginate hydrogels of varied molecular weight distribution enable sustained release of sphingosine‐1‐phosphate and promote angiogenesis

“…Previous work in this field has centered attention on the delivery of growth factors and cytokines, such as vascular endothelial growth factor (VEGF) and stromal cell‐derived factor‐1 (SDF‐1), which play critical roles in regulating tissue homeostasis and regeneration . However, recombinant proteins can be expensive to produce and results thus far have been underwhelming . In alternative, enthusiasm regarding the pursuit of pharmacological strategies involving small molecule lipid mediators, such as sphingosine‐1‐phosphate (S1P), has thus exhibited a prominent increase due to their wide range of effects over multiple cell types and ease of scale‐up in manufacturing .…”

“…However, recombinant proteins can be expensive to produce and results thus far have been underwhelming . In alternative, enthusiasm regarding the pursuit of pharmacological strategies involving small molecule lipid mediators, such as sphingosine‐1‐phosphate (S1P), has thus exhibited a prominent increase due to their wide range of effects over multiple cell types and ease of scale‐up in manufacturing . Therefore, the development of strategies involving the design of biomaterial systems for lipid delivery presents a growing field of research.…”

“…The ability to develop delivery vehicles that control sustained presentation of S1P is particularly important, as the lipid's function is highly dependent upon extensively regulated, endogenous concentration gradients . However, research efforts to present S1P in a controlled fashion have thus far been limited in part due to difficult challenges associated with the lipid's small size, strong hydrophobicity, and rapid metabolic turnover . Thus, there is a growing need for a better understanding of how these material systems may be formulated and tuned to control bioactive lipid release.…”