Novel human-derived extracellular matrix induces in vitro and in vivo vascularization and inhibits fibrosis

Abstract

The inability to vascularize engineered organs and revascularize areas of infarction has been a major roadblock to delivering successful regenerative medicine therapies to the clinic. These investigations detail an isolated human extracellular matrix derived from the placenta (hPM) that induces vasculogenesis in vitro and angiogenesis in vivo within bioengineered tissues, with significant immune reductive properties. Compositional analysis showed ECM components (fibrinogen, laminin), angiogenic cytokines (angiogenin, FGF), and immune-related cytokines (annexins, DEFA1) in near physiological ratios. Gene expression profiles of endothelial cells seeded onto the matrix displayed upregulation of angiogenic genes (TGFB1, VEGFA), remodeling genes (MMP9, LAMA5) and vascular development genes (HAND2, LECT1). Angiogenic networks displayed a time dependent stability in comparison to current in vitro approaches that degrade rapidly. In vivo, matrix-dosed bioscaffolds showed enhanced angiogenesis and significantly reduced fibrosis in comparison to current angiogenic biomaterials. Implementation of this human placenta derived extracellular matrix provides an alternative to Matrigel and, due to its human derivation, its development may have significant clinical applications leading to advances in therapeutic angiogenesis techniques and tissue engineering.

The Placenta as an Organ and a Source of Stem Cells and Extracellular Matrix: A Review

“…Decellularized ECM may augment endogenous stem cell functions and may be used as carriers for stem/ progenitor cells into damaged, diseased or aged tissues and organs [Lutolf et al, 2009], thus fulfilling a broad range of clinical applications. Placental ECM has been applied as a dermal substitute for full-thickness wound healing [Choi et al, 2013], to promote in vitro and in vivo vascularization, and inhibit fibrosis, in lieu of Matrigel [Moore et al, 2015].…”

Human Perinatal‐Derived Biomaterials

“…[13] ELISA assays have identified over 25 cytokines within the vascular bed shown to be directly related to angiogenesis and vascular regulation, including ANG, TGF-β, TNF-α, IGF-1, SDF-1, VEGF, and vWF. [14, 15] Liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis has also identified high concentrations of pro-angiogenic basement membrane components within the placenta including type IV collagen, heparin sulfate, desmosomes, fibrillin, laminin, and fibronectin. [15]…”

“…[14, 15] Liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis has also identified high concentrations of pro-angiogenic basement membrane components within the placenta including type IV collagen, heparin sulfate, desmosomes, fibrillin, laminin, and fibronectin. [15]…”

“…[20] Analysis has also shown the presence of neutrophil defensin (DEFA1), an antimicrobial peptide, within placental tissue. [21] The antimicrobial properties of the placenta are likely the result of multiple molecular interactions that work simultaneously to inhibit microbe growth and endotoxin activity. Further development of novel antimicrobial therapies derived from placental tissues are likely as more in-depth mechanistic studies are completed.…”

Tissue engineered micro and macrovasculature utilizing stromal vascular fraction.

“…Indeed, while tip cell percentage remains high in the presence of DAPT, and ZM 306416, stalk cell percentages decrease significantly in the presence of ZM 306416 and Imatinib mesylate at 60h of incubation ( Figure 5D). Indeed, endothelial cell and mural cell self-assembly and proliferation is required to form functional microvasculature, however, extracellular matrix (ECM) components are necessary to stimulate cell growth and maturation 153,154 . Fully mature vascular networks restructure surrounding ECM, via matrix metalloproteases, to create a distinct basement membrane composed predominantly of type IV collagen and laminins 121 and 332;…”