Platelet and plasma bioactive scaffolds for stem cell differentiation: What are we missing?

• Bioactive scaffolds
• extracellular matrix
• fibronectin
• platelet based scaffolds
• platelet-rich plasma
• stem cells

To the editor,

Tissue engineering has evolved rapidly over the past 10 years and hold great promise for the treatment of several health injuries, especially due to the accumulated knowledge in stem cell biology, cultivation techniques and differentiation capabilities [1]. Many tissues to be generated in vitro require three dimensional (3D) scaffolds for the successful differentiation of stem cells into the target/desired cell phenotype, such as cartilage tissue and others [1, 2]. Due to this escalating demand, scaffolding technology for cell culture/therapy now allows for more efficient approaches, notably the employment of bioactive materials as their major constituents [2].

One recently published report at this journal demonstrated the feasibility of using platelets as the main component of a bioactive 3D constructed scaffold for mesenchymal stem cell (MSC) cultivation [2]. This scaffold has been found to be suitable for the differentiation of the referred cells in chondrocytes, as demonstrated using extracellular matrix characterization [2] and molecular biology techniques [3]. Moreover, its main component is easy to access, especially in blood transfusion centers. Although this scaffold has been systematically considered to be bioactive largely due to the growth factors, such as PDGF, VEGF, FGF, TGF-β, and others, present at platelets’ granules [3], to date, no one has ever considered a role for plasma fibronectin, as a bioactive agent, which could deliver extra differentiation cues for stem cells cultivated inside these scaffolds.

Interestingly, accumulated evidence shows that fibronectin, an abundant protein present at blood plasma, bounded to platelets, and extracellular matrix (ECM), is able to actively modify the biology behavior of both stem [4] and tumoral cells [5]. In this sense, it has been reported that traits such as the activity of matrix metalloproteinases (MMPs), important endopeptidases related to ECM remodeling, which could not be detected at the conditioned medium of prostate normal and tumoral human cells, rapidly increases after short time exposure to fibronectin [5]. Given that the 3D scaffold structure needs to be reabsorbed, as the EMC proteins are produced by the seeded cells, this stimulus on MMP activity could be beneficial during the remodeling of the 3D structure. Moreover, stem cells cultivated at bone differentiation medium exhibited enhanced alkaline phosphatase activity and calcium deposition after exposure to fibronectin coated to culture plates [4], which backs up a possible differentiation role of fibronectin in platelet-derived scaffolds, as a synergistic inductor effect to the stimulus provided from the aforementioned growth factors.

Also very relevant, other bioactive scaffolds such as those derived from fibrin sealants are commonly used for stem cell differentiation protocols [6]. For a detailed review on these scaffolds and their applications for regenerative medicine, readers are advised to seek a recently published report [7]. These products, which are commercially available [8, 9] or obtained with an automated device for the production of fibrin sealant [9], have been characterized (nevertheless of the method of obtention) as being enriched in fibronectin content, as observed through the use of specific antibodies and sodium dodecyl sulphate–polyacrylamide gel electrophoresis [9]. Therefore, protocols that employ these scaffolds should also take into consideration the possible influence of fibronectin, on the stimulus provided to the differentiation of the seeded stem cells and their MMPs expression/activity.

However, this protein could also exert a proliferative induction of stem cells cultivated in platelet constructed scaffolds, as there are reports of higher proliferation of CD34⁺ cells when fibronectin supplementation was employed [10]. On this view, a differentiation stimulus to the target cells would be an unlikely event to happen.

In conclusion, there may be a possible role for the remaining plasma fibronectin, as an extra differentiation inductor, which can also modulate the remodeling of the constructed tissue via MMPs activity, in platelet/plasma-based scaffolds used for stem cell differentiation purposes. Future investigators should be aware of this in their future endeavors with these scaffolds for regenerative medicine research protocols.

Declaration of interest

The author reports no conflict of interest.

Acknowledgements

We would like to thank Mr Chris Gieseke at University of Texas at San Antonio, for providing excellent assistance in the English language revision of this article. The authors also greatly acknowledge Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq, for a post-doctoral fellowship granted to A.M. (process n. 151248/2013-3).