Lysophosphatidic Acid Enhances Stromal Cell-Directed Angiogenesis

Abstract

Ischemic diseases such as peripheral vascular disease (PVD) affect more than 15% of the general population and in severe cases result in ulcers, necrosis, and limb loss. While the therapeutic delivery of growth factors to promote angiogenesis has been widely investigated, large-scale implementation is limited by strategies to effectively deliver costly recombinant proteins. Multipotent adipose-derived stromal cells (ASC) and progenitor cells from other tissue compartments secrete bioactive concentrations of angiogenic molecules, making cell-based strategies for in situ delivery of angiogenic cytokines an exciting alternative to the use of recombinant proteins. Here, we show that the phospholipid lysophosphatidic acid (LPA) synergistically improves the proangiogenic effects of ASC in ischemia. We found that LPA upregulates angiogenic growth factor production by ASC under two- and three-dimensional in vitro models of serum deprivation and hypoxia (SD/H), and that these factors significantly enhance endothelial cell migration. The concurrent delivery of LPA and ASC in fibrin gels significantly improves vascularization in a murine critical hindlimb ischemia model compared to LPA or ASC alone, thus exhibiting the translational potential of this method. Furthermore, these results are achieved using an inexpensive lipid molecule, which is orders-of-magnitude less costly than recombinant growth factors that are under investigation for similar use. Our results demonstrate a novel strategy for enhancing cell-based strategies for therapeutic angiogenesis, with significant applications for treating ischemic diseases.

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

“…Indeed, human adipose-derived stromal cells (ASCs) entrapped in fibrin gels containing LPA significantly improved recovery and functional outcome in a mouse model of critical limb ischemia. 9 Two weeks after femoral artery ligation and resection, animals treated with both fibrin-entrapped ASCs and LPA showed significantly increased blood vessel formation compared with mice treated with only ASCs or LPA, while all groups receiving LPA exhibited reduced limb necrosis and loss. 4 Intermittently repeated, local injections of sphingosine-1-phosphate (S1P)-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles (PLGA-S1P) resulted in enhanced blood flow recovery in murine ischemic hindlimbs after 28 days in vivo when examined by Laser Doppler blood flow analysis (B).…”

“…2,14 These lipids have been incorporated into biomaterials for in vivo delivery 4,9,11,15,16 and are several orders of magnitude cheaper than recombinant proteins. 9 Here, the effects of LPA and S1P on both cellular-and tissue-level phenotypes are surveyed, with an eye toward regulating stem/ progenitor cell growth and differentiation. In particular, this review examines work that has translational applications for cell-based tissue engineering strategies.…”

Metabolomics Predicts Neuroimaging Characteristics of Transient Ischemic Attack Patients

“…These molecules, and their signaling through their cognate receptor LPA1, have been implicated in the generation of ischemia-related neuropathic pain (Halder et al, 2013). Moreover, some molecules from this family are also considered angiogenic factors (Ren et al, 2011, Binder et al, 2013). Therefore, diminished levels may be associated with a lower capacity to withstand hypoxia-induced apoptosis (Liu et al, 2009).…”

Mesenchymal Stem Cell Paracrine Factors in Vascular Repair and Regeneration

“…LPA promotes VEGF secretion by human MSCs and this effect is enhanced under hypoxia, making LPA a natural target for stimulating trophic factor secretion and endothelial cell recruitment in ischemic defects [110]. LPA upregulated angiogenic growth factor production by MSCs under two- and three-dimensional in vitro models of serum deprivation and hypoxia (SD/H), and that these factors significantly enhanced endothelial cell migration [110]. Transplantation of LPA treated MSCs increased capillary density in the myocardium and improved myocardial function in the ischemic heart.…”

“…Fibrin gels incorporated with Lysophosphatidic Acid (LPA) were used as carriers of MSCs to enhance revascularization in hindlimb ischemia. Adipose derived MSCs responded to LPA when incorporated to fibrin gels without any preconditioning regimens [110]. …”