By adding an enzyme to adult stem cells 'in vitro', remarkable results can be booked 'in vivo', say scientists of the University of Twente in The Netherlands. Up to now, so-called mesenchymal stem cells could not succesfully be used to create new bone tissue, e.g. for repair. By adding PKA enzyme to the stem cells beforehand, a substantial amount of bone is grown after implanting the cells.

Hitherto it has been difficult to induce adult human stem cells to produce bone, e.g. in order to repair bone tissue. Researchers at the University of Twente have shown that if the enzyme PKA is previously activated in the stem cells in the lab, following implantation this results in substantial bone formation. This opens up new ways of repairing bone tissue using cell material from the patient.

In animals, ‘adult’ mesenchymal stem cells have already been used successfully to grow fresh bone. Bone formation using human adult stem cells, e.g. from bone marrow, has been less successful, which has hitherto limited the alternatives hospitals can offer for repairing damaged tissue other than spontaneous healing. Activating the PKA enzyme prior to implantation, however, produces a dramatic improvement in ‘in vivo’ bone growth. The cells can be observed maturing into bone cells already in the lab; once sown on a carrier and implanted in a mouse, the bone grows well.

The enzyme protein kinase A (PKA) is responsible for many processes in a cell. The messenger ‘cyclic AMP’ activates PKA: adding it to the stem cells ensures that they stimulate one another, the researchers think. Not only does cyclic AMP promote maturation into bone cells; the cells themselves also secrete various substances that stimulate bone growth. This may explain why mesenchymal stem cells treated with cyclic AMP form significantly more bone than those without the stimulus.

The advantage of administering a bone-growth-stimulating substance in advance is that it can be removed just before implantation. Experiments to date have mainly used high concentrations of a bone-growth-stimulating hormone, e.g. incorporated in the carrier on which the cells are ‘sown’. In the new approach not only are the hormone concentrations lower, they also more closely resemble the cocktail of hormones normally involved in bone growth.

This is the second time in a short space of time that the researchers, led by Dr Jan de Boer, have published in PNAS: earlier this month they published an article on a major breakthrough in the use of embryonic stem cells to grow bone. Both methods are promising when it comes to repairing bone tissue in future using cells from the patient’s own body. Compact bioreactors will be developed to grow cells quickly into tissue that can be used in the operating theatre.

The research was carried out at the Tissue Regeneration Department of the University of Twente’s Institute for Biomechanical Technology (BMTI). The researchers collaborated with fellow scientists at UMC Utrecht and the Erasmus Medical Center in Rotterdam.

Article: Ramakrishnaiah Siddappa, Anton Martens, Joyce Doorn, Anouk Leusink, Cristina Olivo, Ruud Licht, Linda van Rijn, Claudia Gaspar, Riccardo Fodde, Frank Janssen, Clemens van Blitterswijk, and Jan de Boer, 'cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo', PNAS May 20, 2008 vol. 105 no. 20 7281-7286 10.1073/pnas.0711190105