Figure 1. Stem Cell–Recruiting Hydrogels Based on Self-Assembling Peptides
Figure 1. Stem Cell–Recruiting Hydrogels Based on Self-Assembling Peptides

The Materials for Biomaterials session Best Contribution Award presented by Steve Zinkle goes to Youngmee Jung, Korea Institute of Science and Technology, for the oral presentation ’Self-assembling peptide nanofiber coupled with neuropeptide substance P for stem cell recruitment’.

As a winner of the above Materials Today Asia Contribution Award, Yongmee Jung and Soo Hyun Kim discuss their work with us.

Stem cell–based therapy in regenerative medicine may be one of the best approaches for wound healing and tissue regeneration. Many studies have shown that the trophic effects of transplanted stem cells enhance the treatment of lung, liver, and skin injuries, as well as myocardial infarction [1]. However, although stem cell transplantation—including cell isolation and cell culture in vitro—results in a good prognosis, there are some limitations, such as high cost, invasiveness, the shortage of cell sources, and the risk of tumorigenesis [2]. To overcome these limitations, technologies for recruiting endogenous stem cells to the site of injury may provide another promising approach, mimicking in situ tissue regeneration by the body’s own wound healing process. Unlike cell-based therapies, this strategy does not need outside cell sources or in vitro cell manipulation. Host stem cells can be mobilized using granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or stromal cell–derived factor-1 alpha (SDF-1α), each of which upregulates adhesion molecules and activates chemokine signaling [3]. It has been reported that substance P (SP), another candidate for recruitment of host stem cells, is an injury-inducible factor that acts early in the wound healing process to mobilize CD29+ stromal-like cells, and thus could be used for tissue regeneration [1].

To achieve effective delivery of SP for an extended period and improve the engraftment of recruited cells at the injured site, scaffolds can be constructed from hydrogels with microenvironments similar to the native tissue. Of particular interest are self-assembling peptide (SAP)–based hydrogels, which are typically composed of alternating hydrophilic and hydrophobic amino acids organized into 5–10 nm fibers and assembled into three-dimensional nanofibrous structures under in vivo conditions [4]. The resulting structure resembles nanostructured environments such as collagen hierarchical structures that promote adhesion, proliferation, and differentiation of cells. Furthermore, SAP is versatile enough to incorporate specific motifs based on the desired function with chemical coupling by peptide bond [5].

Recently, we designed bioactive peptide hydrogels that are able to recruit mesenchymal stem cells by coupling SAP to SP. The mixture of SAP and SP-coupled SAP can successfully maintain its nanofibrous structure and be assembled into a 3D scaffold at physiological conditions.

We confirmed the ability of this SP-coupled SAP to attract stem cells both by in vitro cell migration assay and by in vivo real-time cell tracking assay. In vitro, many cells migrated through the 8-μm membrane pores and settled onto the lower surfaces of Transwell plates under the influence of SP-coupled SAP. In vivo, we injected the hydrogels into the subcutaneous tissue in nude mice and injected labeled human mesenchymal stem cells (hMSCs) into the tail vein. The migration of the injected cells was tracked in real time using a multispectral imaging system, which demonstrated that the labeled hMSCs supplied via intravenous injection were recruited to the hydrogel-injected site (Figure) [6].
We then applied our bioactive peptide hydrogels, SAP coupled with SP, to several disease models to evaluate their stem cell recruitment abilities and treatment effects on injured tissues. We have studied the effects of these hydrogels on animal models of ischemic hind limb, calvarial defect, myocardial infarction, osteoarthritis, and skin wounds. We observed in each case that in the group treated with SP-coupled peptide hydrogels, many MSCs were recruited to the injured sites, and cell apoptosis and fibrosis of injured tissues were both conspicuously decreased. Moreover, the regeneration of site-specific tissues was enhanced with the injection of stem cell–recruiting peptide hydrogels in various defect models, and tissue functions were accordingly improved without cell transplantation [2, 5, 6].
In conclusion, we have developed injectable bioactive peptides that can recruit MSCs and have evaluated their therapeutic potential on animal defect models. By applying these peptide hydrogels, we were able to deliver SP over an extended period and provide 3D microenvironments to injured regions, allowing bioactive peptides to recruit MSCs successfully, prevent cell apoptosis, and promote tissue regeneration leading to a full recovery of defects. We expect that stem cell–recruiting hydrogels based on SAP could be one of the most powerful tools for tissue regeneration without cell transplantation through the recruitment of endogenous stem cells.

‘This work was supported by the KIST Institutional Program’

1. H. S. Hong, et al., Nat. Med., 15 (2009), pp. 425–435
2. J. H. Kim, et al., Biomaterials, 34 (2013), pp. 1657–1668
3. T. Lapidot, I. Petit, Exp. Hematol., 30 (2002), pp. 973–981
4. S. Zhang, et al., Semin. Cancer Biol., 15 (5) (2005), pp. 413–420
5. J. E. Kim, et al., Int. J. Nanomedicine, 9 (Suppl 1) (2014), pp. 141–157
6. S. H. Kim, et al., Tissue Eng. Part A, E-Pub (2014)