Stem cells initiate cartilage regeneration, but do not participate in it

Researchers from the Vetmeduni Vienna (Veterinärmedizinische Universität Wien), Austria, found that mesenchymal stem cells are not involved in the restoration of cartilaginous tissue, but only control this process by attracting endogenous cells. The article with the results of the discovery was published in the October issue of JCI-Insight.

Therapy with mesenchymal stem cells, the so-called precursor cells of connective tissue, has a powerful potential for curing of cartilage damages. However, it is still unclear whether they participate directly in the regeneration or whether they trigger the process.

Austrian researchers were able to resolve this issue using a new natural model. After the injection, the stem cells organized the treatment with endogenous cells, but themselves they did not participate in the regeneration of the cartilage. To implement this discovery, scientists blocked the immune response to the molecule necessary to track the injected cells.

The problem of the researchers was that the marker protein was perceived by the recipient’s immune system as a foreign protein, leading to the rejection of the transplanted stem cells. But scientists were able to overcome this limitation.

“To date, it has not been possible to show what an injection of stem cells really does in an animal model,” – explains Reinhold Erben, the senior author of the study. “The problem is that you have to track the cells with particular proteins that the immune system of the recipient recognizes as non-endogenous and thus potentially harmful. The resulting rejection of the injected cells has prevented the validation of their mode of action.”

So, the ability to track stem cells existed only on models of immunodeficient animals that did not respond to proteins due to a genetically reduced immune system. These models could not give complete information about the mechanism of action of stem cells.

“We therefore worked with a ‘lifelike’ animal model that is immunocompetent but shows no response to our tracker molecule. This enabled us to show that stem cells have a purely modulating action in the treatment of cartilage damage,” – says Erben.

“We developed a so-called double-transgenic animal model for the purpose,” – notes Erben.

Special donor and recipient lines of mice and rats were bred that expressed an artificially inserted human cell-surface protein, the placental alkaline phosphatase, ALPP, on all their cells to enable them to be traced. In addition, the ALPP of the recipient line differed from that of the donors at an only one amino acid. In addition, both variants of proteins are almost identical, the immune system could not distinguish its own cells from donor cells.

“Moreover, the mutation inactivates the otherwise heat-stable protein at high temperatures, allowing the recipient cells to be differentiated from the donor cells during the experiment,” – explains Erben.

The idea of using such a protein both for detecting molecular labels and for deceiving the recipient’s immune system can be applied to other animal models.

In addition, the use of a dual transgenic system without loss of immunocompetence should support the study of stem cells in treatments other than cartilage regeneration.

“Our results contribute to our understanding of stem cell therapy, as they show for the first time that therapy stimulates the body’s own cells to promote the regeneration of damaged connective tissue, such as cartilage,” – concludes Erben.