In situ cardiovascular tissue engineering: investigating the initiation & early tissue formation

Description

In situ tissue engineering is emerging as a new approach to provide living, functional and healthy cardiovascular replacement tissues by using the regenerative potential of the human body. It is the aim of the in situ TE approach to design of-the-shelf available, synthetic, biodegradable scaffolds capable of controlling the regeneration process by (selectively) recruiting endogenous cells into the scaffold and guiding  tissue formation and remodeling. However, in order to design these scaffolds it is required to have a profound understanding of the mechanisms underlying successful regeneration.
When implanted in vivo,  scaffolds are exposed to a series of inflammatory events orchestrated by cells and signaling molecules of the wound healing response and the foreign body response.
It is hypothesized that these inflammatory events form the key for modulating and controlling cell and tissue fate. By elucidating the (early) inflammatory host response we might be able to identify target cells and important signaling molecules that can be used in immunomodulatory scaffold development.  

One of these key players in the early inflammatory response is the signaling molecule Monocyte Chemotactic Protein (MCP-1); a chemokine that regulates monocyte/macrophage migration and infiltration [1]. It was seen that an early burst release of MCP-1 incorporated in fibrin and seeded on an electrospun poly(ε-caprolactone) (PCL) scaffold resulted in improved neotissue formation and organization in vivo. Although these outcomes suggest a prominent role for the circulating cells in tissue regeneration that is positively influenced by a MCP-1 burst release, the exact mechanisms of the in situ cardiovascular tissue engineering cascade remain to be clarified [2].
It is the aim of this project to investigate these mechanisms of tissue regeneration to contribute to immunomodulatory scaffold development. More specifically, research will be performed to gain insights in the temporal circulating cell influx and cytokine production and their role in cell differentiation and tissue formation during the early natural human host response.

A mesofluidics-based in vitro test platform, mimicking the hemodynamic environment [3], can be used to systematically study the effects of scaffold properties, e.g. MCP-1 dose and release, on circulating cell recruitment and subsequent tissue development under physiological circumstances. In addition, chemotaxis experiments can be performed to gain insights in the process of cell mobilization from lymphoid tissue, since mobilized (progenitor) cells may play a detrimental role in tissue regeneration [4]. The exact project will depend on the current status of this research line.

References

  1. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–26.
  2. Smits A, Talacua H, Muylaert D, et al. Improved in situ arterial tissue engineering by circulating cells via an immunomodulatory scaffold with local MCP-1 release. 2014. *submitted*
  3. Smits AIPM, Driessen-Mol A, Bouten CVC, Ph D, Baaijens FPT. A Mesofluidics-Based Test Platform for Systematic Development of Scaffolds for In Situ Cardiovascular Tissue Engineering. Tissue Eng Part C. 2012;18(6).
  4. Smits AIP., Ballotta V, Driessen-Mol A, Bouten VC., Baaijens FP. Shear flow affects selective monocyte recruitment into MCP-1-loaded scaffolds. J Cell Mol Med. 2014;20(10):1–13.

Researchers

Researchers: T.B. (Tamar) Wissing.
Supervisors: A.I.P.M. (Anthal) Smits, A. (Anita) Driessen-Mol, C.V.C. (carlijn) Bouten.

Funding by CVON (Cardiovascular Research Netherlands) and De Hartstichting (Heart Foundation).