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Stem cells conduct cartilage regeneration but are not directly involved

Therapy with mesenchymal stem cells, the so-called progenitor cells of connective tissue, holds great promise for the regeneration of cartilage tissue. But how stem cell therapy contributes to the healing of damaged connective tissue has been unclear. Debate has centered on whether the injected cells promote regeneration or stimulate the body's own cells to proliferate.

A new strategy has now enabled researchers from the Department of Biomedical Sciences at the University of Veterinary Medicine (Vetmeduni), Vienna, to solve the question.

The problem was that a marker protein was recognized by the immune system of the recipient as a non-self protein, leading to the rejection of the injected stem cells. The Vetmeduni scientists were able to overcome this limitation and show that progenitor cells do not participate directly in cartilage regeneration, but serve to "animate" the process.

"To date, it has not been possible to show what an injection of stem cells really does in an animal model," explained Reinhold Erben, M.D., DVM, the senior author of the study published recently in JCI-Insight. "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.”

To overcome this, the research team developed special donor and recipient lines of mice and rats that expressed an artificially introduced 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 a single amino acid. As the two protein variants are almost identical, the immune system cannot distinguish the body's own cells from those of the donor.

"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," Dr. Erben explained.

The idea of using a protein variant both to enable the detection of the tracking molecule and to deceive the immune system of the recipient lines can be applied in other animal models. ALPP – like the green fluorescent protein, GFP and luciferase – is commonly used as a marker protein. “Unlike other tracking molecules, the two variants represent the perfect combination for stem cell research,” said Dr. Erben.

The use of a double transgenic system without the loss of immunocompetence should support stem cell research in fields 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," Dr. Erben concluded.

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DOI: 10.1172/jci.insight.87322