Researchers from Stellenbosch University (SU) are exploiting the guerrilla tactics used by hard-core bacteria, such as those causing Tuberculosis, to develop 'cellular taxis' that will be able to deliver stem cells in a relatively short time to any injured tissue.

Superbugs like the Tuberculosis bacterium is able to paralyse the body's immune system and hide in immune cells without being destroyed by it.

The three-year project is funded by the Blue Skies funding initiative of South Africa's National Research Foundation. This initiative supports "multi-dimensional, self-initiated, curiosity-driven inquiry that necessitates high investment risks, addresses new phenomena and pushes the frontiers of knowledge".

Prof. Carine Smith, a stress immunologist from the Department of Physiological Sciences at SU and project leader, is working with Prof. Kathy Myburgh, holder of a new South African research chair (SARChI) in Skeletal Muscle Physiology, Biology and Biotechnology, and Prof. Bert Klumpermann, holder of the South African research chair (SARChI) in Advanced Macromolecular Architectures.

Prof. Smith explains their approach: "We already know that our immune system manufactures large cells – called macrophages – to fight infections. These large cells literally recognise, engulf and then destroy invaders in a process we call phagocytosis (the process by which a cell engulfs material either to destroy it, to feed on it, or to get information from it).

"However, superbugs like the bacteria causing TB and Listeriosis have managed to sabotage this process by paralysing the immune system just after it has been engulfed by a macrophage. In this way the invader hides away in the macrophage without being destroyed by it".

"Ours is a novel approach to exploit this process for targeted stem cell delivery in regenerative medicine – we plan to use the highly mobile macrophages as shuttle to deliver stem cells, unharmed, to regeneration sites."

The expertise from each of the three researchers and their research groups are crucial to the project.

Milestones reached in the first year

From laboratory studies, Prof. Smith's group has so far successfully altered the macrophages chemically to prevent the stem cells from being digested, while not compromising the motility of the macrophages or their ability to phagocytose cells.

Prof. Bert Klumpermann explains his role as follows: "The idea is to cover the stem cell with a polymer layer in order to maintain it until it is delivered to the regeneration site. The polymer must be designed to have several properties. Firstly, it has to behave correctly in bodily fluids and at body temperature – this is very different from 'bench chemistry'. Secondly, it must recognise elements of the stem cell surface proteins in order to polymerise around the stem cell. Lastly, it must then be easily engulfed by the macrophages that will deliver this cargo."

 Prof Myburgh's group, which studies muscle injuries and regeneration, has also successfully isolated the satellite stem cells from mouse muscle and from human muscle biopsies and multiplied them in the laboratory.

"In 2016 we will focus on the aspect of priming the cells for rapid fusion at the site of the injury, a process that will have to precede them being engulfed by the manipulated macrophages" she explains.

"At first, as proof of concept, the stem cells will be delivered close to the site of injury to maximise delivery success, but ultimately we would like to deliver via injection into the blood stream, utilising the sensing machinery inherent to the macrophage that allows it to find an injury site," she explains.

As if that is not enough, Prof. Smith's group then needs to determine how easily the macrophages can release their cargo at the target site; Prof. Klumperman's group has to determine if their synthetic coating around the stem cell will depolymerise in the tissue conditions at the site of the injury; and Prof. Myburgh's group must determine if the delivered satellite stem cells regenerate muscle better than in a control group of mice who must use their own satellite cells.

The individual research groups have now reached a point where they can begin to test the interactions between their research products – modified biological macrophages, synthetic polymer and isolated fully functional stem cells – this exciting phase is scheduled to kick off early in 2016.

Prof. Smith says receiving the Blue Skies grant has been an outstanding privilege: "It is immensely exciting to work at the cutting edge of science on a project that most grant application referees would have considered too risky to fund. The progress we have made so far in reaching the first milestones fully justifies the investment the NRF has made.

"We are literally witnessing our 'unimaginable' ideas taking form right in front of our eyes."

Above, time-lapse images of three modified macrophages, captured using confocal microscopy in the Central Analytical Facilities unit at Stellenbosch University. The macrophage in the centre contains numerous fluorescent-red labelled latex beads (representing a stem cell) without digesting the red protein on the bead surface. At the bottom, a macrophage can be seen extending its pseudopod to grab on to two "stem cells" and ingest them.  Images: Stellenbosch University

Contact details
Prof. Carine Smith
E: csmith@sun.ac.za
T: +27 _21 808 4388