Tissue regeneration operates differently than expected

August 05, 2005

Max Planck researchers in Bad Nauheim discover the mechanism by which adult stem cells are integrated into skeletal or heart muscle tissue

There is disagreement, however, about the mechanism on which repair processes are based. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, in co-operation with colleagues from Martin Luther University in Halle-Wittenberg, have now shown that skeletal muscle tissue can fuse with adult stem cells, via a mechanism based on the participation of mediators which are generally involved in immune cell activation. Although being unable to transdifferentiate into completely functional muscle cells, they are integrated into the tissue complex by fusing with differentiated tissue cells. In contrast, in the heart muscle tissue the mechanism seems to be different from this. The scientists in Bad Nauheim conclude from their study that adult stem cells are involved in tissue repair processes in a paracrine way by delivering mediating factors rather than by simply becoming components of the regenerating organ. (Genes & Development, August 2005).

Stem cells are fully unspecialised cells which can develop into all kinds of cell types. Embryonic stem cells provide the origin of a developing 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 the influence of certain growth factors.

Other stem cells - adult stem cells - play an important role throughout an organism's life. For example, bone marrow stem cells provide for the replenishment of short-lived blood cells. Adult stem cells can be found locally in various tissues and organs, and we have presumed that they are participating in the repair and maintenance of organ functions.

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

Scientists led by Thomas Braun, Director of the Max Planck Institute for Heart and Lung Research, have discovered by a number of different experimental approaches that mesenchymal stem cells only show a rudimentarily developed potential for transdifferentiation processes. All cases in which functional skeletal muscle cells arose from mesenchymal stem cells were based on the fusion of stem cells with already differentiated muscle cells.

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

Fully-functional muscle cells only developed after the mesenchymal stem cells were cultivated together with skeletal or heart muscle cells. This was indicated by the green fluorescence of muscle cells derived from the fusion with a stem cell which before had been labelled with the green dye. In contrast, no green fluorescing muscle cells became evident when stem and muscle cells were spatially separated by a membrane between both cell types. The researchers conclude that this experiments proofs that cell fusion of mesenchymal stem cells and muscle cell but not their transdifferentiation forms the basis for the regeneration mechanism. Additional experiments were focussing on the molecular mechanism underlying the cell fusion process. In these investigations, so-called "chimeric" mouse embryos were produced from mesenchymal stem cells and several mouse mutants: Obviously, the stem cells are recruiting the IL-4/NFAT signalling pathway which also is involved in the activation of T-lymphocytes during immune response.

From the findings presented by Thomas Braun and his collaborators some important consequences for the use of adult stem cells in possible therapeutic approaches could arise, since they contradict the predominant opinion that bone marrow-derived or local stem cells are involved in the regeneration of heart and skeletal musculature by transdifferentiating into muscle cells. By fusing with the cells of the regenerating tissue these cells rather seem to only simulate such a transdifferentiation mechanism. This has major implications for the prospects of stem cell therapies targeting on the regeneration of skeletal or heart musculature.

Max-Planck-Gesellschaft

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