Tissue Regeneration Operates Differently Than Expected

There is disagreement, however, about the mechanism on which repairprocesses are based. Scientists from the Max Planck Institute for Heartand Lung Research in Bad Nauheim, Germany, in co-operation withcolleagues from Martin Luther University in Halle-Wittenberg, have nowshown that skeletal muscle tissue can fuse with adult stem cells, via amechanism based on the participation of mediators which are generallyinvolved in immune cell activation. Although being unable totransdifferentiate into completely functional muscle cells, they areintegrated into the tissue complex by fusing with differentiated tissuecells. In contrast, in the heart muscle tissue the mechanism seems tobe different from this. The scientists in Bad Nauheim conclude fromtheir study that adult stem cells are involved in tissue repairprocesses in a paracrine way by delivering mediating factors ratherthan by simply becoming components of the regenerating organ. (Genes& Development, August 2005).

Stem cells are fully unspecialised cells which can develop into allkinds of cell types. Embryonic stem cells provide the origin of adeveloping organ, during the growth of an embryo. For example,mesenchymal cells -- stem cells from embryonic connective tissue --transform themselves during embryogenesis into muscle cells, under theinfluence of certain growth factors.

Other stem cells -- adult stem cells -- play an important rolethroughout an organism's life. For example, bone marrow stem cellsprovide for the replenishment of short-lived blood cells. Adult stemcells can be found locally in various tissues and organs, and we havepresumed that they are participating in the repair and maintenance oforgan functions.

The controversial idea is that adult stem cells have thepotential for transdifferentiation; in other words, that they are ableto transmutate from one type of organ cell to another. If that is thecase, bone marrow cells would be able to change into lots of differentkinds of tissue cells -- for example, skeletal muscle cells.

Scientists led by Thomas Braun, Director of the Max PlanckInstitute for Heart and Lung Research, have discovered by a number ofdifferent experimental approaches that mesenchymal stem cells only showa rudimentarily developed potential for transdifferentiation processes.All cases in which functional skeletal muscle cells arose frommesenchymal stem cells were based on the fusion of stem cells withalready differentiated muscle cells.

Although, like the researchers from Bad Nauheim show,cultivated mesenchymal stem cells are able to express a number ofheart- and skeletal muscle specific genes and undergo some morphologicchanges, after they are co-cultured with growth-factor producing feedercells, finally they did not become entirely functional muscle cells.

Fully-functional muscle cells only developed after themesenchymal stem cells were cultivated together with skeletal or heartmuscle cells. This was indicated by the green fluorescence of musclecells derived from the fusion with a stem cell which before had beenlabelled with the green dye. In contrast, no green fluorescing musclecells became evident when stem and muscle cells were spatiallyseparated by a membrane between both cell types. The researchersconclude that this experiments proofs that cell fusion of mesenchymalstem cells and muscle cell but not their transdifferentiation forms thebasis for the regeneration mechanism. Additional experiments werefocussing on the molecular mechanism underlying the cell fusionprocess. In these investigations, so-called "chimeric" mouse embryoswere produced from mesenchymal stem cells and several mouse mutants:Obviously, the stem cells are recruiting the IL-4/NFAT signallingpathway which also is involved in the activation of T-lymphocytesduring immune response.

From the findings presented by Thomas Braun and hiscollaborators some important consequences for the use of adult stemcells in possible therapeutic approaches could arise, since theycontradict the predominant opinion that bone marrow-derived or localstem cells are involved in the regeneration of heart and skeletalmusculature by transdifferentiating into muscle cells. By fusing withthe cells of the regenerating tissue these cells rather seem to onlysimulate such a transdifferentiation mechanism. This has majorimplications for the prospects of stem cell therapies targeting on theregeneration of skeletal or heart musculature.