Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing

Abstract

Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. Here, we show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin-binding domains (HBDs) located in the α chain laminin-type G (LG) domains. These domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We explore the application of these multifunctional laminin HBDs in wound healing in the type-2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrices improves retention of GFs and significantly enhances the efficacy of vascular endothelial cell growth factor (VEGF-A165) and platelet-derived growth factor (PDGF-BB) in promoting wound healing in vivo, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterial matrices as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.

Boosting the biogenesis and secretion of mesenchymal stem cell-derived exosomes

“…Assembly of collagen fibrils, as well as integrin dependent and independent binding are both necessary for propagation of wound healing responses after injury. Bioinformatic pathway analyses also yielded gene hit counts against laminin-dependent pathways, further supporting our in vitro data, as laminins play a critical role in reepithelization and angiogenesis [31]. The up-regulated proteins used for pathway prediction analysis are directly in line with the angiogenesis, macrophage, and tube formation assay, as they are all involved with exosomal binding to ECM proteins and promotion of wound-healing effects [32][33][34].…”

Targeted Drug Delivery via the Use of ECM-Mimetic Materials

“…Also, the Werner group investigated RGD-functionalized star PEG-heparin hydrogels with a variable degree of heparin sulfation for controlled release of angiogenic growth factors from the hydrogel and capture of inflammatory chemokines in the hydrogel for the chronic wound healing applications (Freudenberg et al, 2015;Lohmann et al, 2017). In addition, the Hubbell group developed laminin-mimetic peptides, which include heparin-binding domains, and employed them to decorate a fibrin matrix for the delivery of VEGF-A165 and platelet derived growth factor PDGF-BB in a chronic wound treatment application (Ishihara et al, 2018). Since the heparin-binding domain in laminin-mimetic peptides has a strong affinity to syndecan cell surface receptors, as well as to VEGF-A165 and PDGF-BB, the system enhanced cell adhesion through interaction with syndecan, and also enabled the sustained release of growth factors from the matrix (Figure 4A).…”

“…In particular, this hybrid strategy will have enormous benefit on the delivery of intracellular therapeutic agents such as nucleic acids, which require DDS to facilitate cellular internalization and prevent the degradation of nucleic acids in the extra-and intracellular environments FIGURE 4 | Extracellular matrix-based matrices and drug interaction-based delivery systems. (A) Growth factor retention in fibrin matrices with laminin-mimetic peptides (α2PI1-8-LAMA33043-3067 or α2PI1-8-LAMA53417-3436) or without peptide (**p < 0.01) (Ishihara et al, 2018). Copyright 2018.…”

Biologically Inspired, Cell‐Selective Release of Aptamer‐Trapped Growth Factors by Traction Forces

“…The use of aptamers also provides a high level of growth factor selectivity via an affinity-based approach,[38] which is not possible through the use of more promiscuous strategies where the binding domains are derived from various components of the ECM. [39,40] Additionally, the ability to abrogate binding affinity via force enables the use of high-affinity aptamers (sub-nanomolar affinities) that prevent significant nonspecific release. These features create intriguing possibilities for multiplexing the on-demand delivery of multiple, well-defined growth factors in order to facilitate synergistic signaling.…”