Tethering QK peptide to enhance angiogenesis in elastin-like recombinamer (ELR) hydrogels
The development of new capillary networks in engineered constructs is essential for their survival and their integration with the host tissue. It has recently been demonstrated that ELR-based hydrogels encoding different bioactivities are able to modulate their interaction with the host after injection or implantation, as indicated by an increase in cell adhesion and the ability to trigger vascularization processes. Accordingly, the aim of this study was to increase their angiogenic ability both in vitro and in vivo using a small VEGF mimetic peptide named QK, which was tethered chemically to ELR-based hydrogels containing cell-adhesion sequences in their backbone, such as REDV and RGD, as well as a proteolytic site (VGVAPG). In vitro studies were performed using a co-culture of endothelial and fibroblast cells encapsulated into the ELR-based hydrogels in order to determine cell proliferation after 21 days of culture, as well as the number of cell-cell interactions. It was found that although the presence of this peptide does not influence the morphological and rheological properties of these hydrogels, it has an effect on cell behaviour, inducing an increase in cell proliferation and the formation of endothelial cell clusters. In vivo studies demonstrate that the QK peptide enhances the formation of prominent functional capillaries at three weeks post-injection, as confirmed by H&E staining and CD31 immunohistochemistry. The newly formed functional microvasculature ensures perfusion and connection with surrounding tissues. These results show that ELR-QK hydrogels increase capillary network formation and are therefore attractive candidates for application in tissue regeneration, for example for the treatment of cardiovascular diseases such as myocardial infarction or ischemia.
The authors are grateful for the funding from the European Commission (NMP-2014-646075, PITN-GA-2012-317306), MINECO of the Spanish Government (PCIN-2015-010, MAT2015-68901-R, MAT2016-78903-R), Junta de Castilla y León (VA015U16) and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar DS. Polymeric scaffolds in tissue engineering application: a review. Int J Polym Sci. 2011;2011:3–7, 10–11.Google Scholar
- 11.Ibáñez‐Fonseca A, Ramos TL, González de Torre I, Sánchez‐Abarca LI, Muntión S, Arias FJ, et al. Biocompatibility of two model elastin‐like recombinamer‐based hydrogels formed through physical or chemical cross‐linking for various applications in tissue engineering and regenerative medicine. J Tissue Eng Regen Med. 2018;12:e1450–e60.CrossRefGoogle Scholar
- 20.Massia SP, Hubbell JA. Vascular endothelial cell adhesion and spreading promoted by the peptide REDV of the IIICS region of plasma fibronectin is mediated by integrin alpha 4 beta 1. J Biol Chem. 1992;267:14019–26.Google Scholar
- 22.Papavasiliou G, Cheng M-H, Brey EM. Strategies for vascularization of polymer scaffolds. J Investig Med. 2010;58:838–44.Google Scholar
- 24.El-Sherbiny IM, Yacoub MH. Hydrogel scaffolds for tissue engineering: progress and challenges. Glob Cardiol Sci Pract. 2013;3:316–42.Google Scholar
- 36.Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. Cold Spring Harb Protoc. 2008;2008:prot4986. pdbGoogle Scholar
- 42.D’Andrea LD, De Rosa L, Vigliotti C, Cataldi M. VEGF mimic peptides: Potential applications in central nervous system therapeutics. New Horiz Transl Med. 2017;3:233–51.Google Scholar