Abstract
The formation of new blood vessels has been shown to be fundamental in the repair of many damaged tissues, and we have recently shown that the adult human periodontal ligament contains multipotent stem/progenitor cells that are capable of undergoing vasculogenic and angiogenic differentiation in vitro and ex vivo. Enamel matrix protein (EMP) is a heterogeneous mixture of mainly amelogenin-derived proteins produced during tooth development and has been reported to be sometimes effective in stimulating these processes, including in clinical regeneration of the periodontal ligament. However, the identity of the specific bioactive component of EMP remains unclear. In the present study we show that, while the high-molecular-weight Fraction A of enamel matrix derivative (a heat-treated form of EMP) is unable to stimulate the vasculogenic differentiation of human periodontal ligament cells (HPC) in vitro, the low-molecular-weight Fraction C significantly up-regulates the expression of the endothelial markers VEGFR2, Tie-1, Tie-2, VE-cadherin and vWF and markedly increases the internalization of low-density lipoprotein. Furthermore, we also demonstrate, for the first time, that the synthetic homolog of the 45-amino acid tyrosine-rich amelogenin peptide (TRAP) present in Fraction C is likely to be responsible for its vasculogenesis-inducing activity. Moreover, the chemically synthesized TRAP peptide is also shown here to be capable of up-regulating the angiogenic differentiation of the HPC, based on its marked stimulation of in vitro cell migration and tubule formation and of blood vessel formation assay in a chick embryo chorioallantoic membrane model ex vivo. This novel peptide, and modified derivatives, might thereby represent a new class of regenerative drug that has the ability to elicit new blood vessel formation and promote wound healing in vivo.
Highlights
The formation of new vascular networks from progenitor cells is considered to be essential for the repair and regeneration of many types of tissue in vivo, including the periodontal ligament (PDL) that supports the teeth [1,2]
Vasculogenic differentiation of progenitor/stem cells into endothelial cells (EC) is considered pivotal in new blood vessel (BV) formation in embryological development and in adult wound healing [1,10], and this process has been reported previously in adult human periodontal ligament cells (HPC) cultured in endothelial basal medium (EBM-2) for 5 weeks [3]
Nificantly higher than the 7.1% positive cells when cultured in EBM-2 alone (p < 0.05). These findings indicate that the tyrosine-rich amelogenin peptide (TRAP) peptide, like Fraction C of enamel matrix derivative (EMD), appears to stimulate HPC vasculogenic differentiation in vitro, comparable to that elicited by the presence of vasculogenic growth factors
Summary
The formation of new vascular networks from progenitor cells is considered to be essential for the repair and regeneration of many types of tissue in vivo, including the periodontal ligament (PDL) that supports the teeth [1,2]. The complex process of neovasculogenesis comprises both vasculogenic and angiogenic differentiation during adult wound healing as well as in developing microenvironments [1,10] Both vasculogenesis, the differentiation of progenitor/stem cells into endothelial cells [1,10,11], and angiogenesis, the development of an organized network of tubular structures originating from endothelial cells (EC) [1,12,10], are regulated in vitro and in vivo by a number of biological mediators, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor, transforming growth factor-beta (TGF-b), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) [1,13,14,15,16,17], and by enamel matrix proteins (EMP) [18,19,20,21,22]
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