Comment on Rüster et al, page 3938

In research as in other human endeavors, there is always a reluctance to accept radically new ideas until the evidence becomes overwhelming. It is not surprising, therefore, that there was great skepticism about initial reports indicating that cells from the bone marrow and other tissues of adult organisms can serve to repair and regenerate tissues.

Henschler and colleagues have provided data to help resolve previously controversial observations about engraftment in vivo of the plastic-adherent cells from bone marrow referred to in the hematologic literature as marrow stromal cells, but first defined as fibroblastoid colony-forming units, then as mesenchymal stem cells, and most recently as multipotent mesenchymal stromal cells (MSCs).1  Henschler et al used a parallel plate flow chamber to demonstrate that MSCs extended podia, rolled, and then formed firm adhesions to endothelial cells in a manner similar to both peripheral blood mononuclear cells and CD34+ hematopoietic progenitors. Therefore, as the authors state, their results established that “MSCs fulfill essential prerequisites for tissue-specific extravasation and homing.” The results move us a step further to understanding how MSCs and related cells from bone marrow have produced encouraging results both in animal models and in clinical trials for several diseases including osteogenesis imperfecta, graft-versus-host disease, and heart disease.

The process of homing, extravasation, and engraftment of MSCs into tissues has been a controversial issue for many years. There have been several reasons for the controversy. One reason is that the experiments first describing engraftment after systemic infusion were carried out in very young mice that had received lethal irradiation.2  Subsequent experiments demonstrated that the levels of engraftment were very low in adult animals that did not have extensive tissue injury.3 

A second reason for the controversy is that MSCs show large interspecies differences and they are particularly difficult to isolate from mice.4  Therefore the results with MSCs from different species were frequently not comparable, and many critical tests in mice were not informative.

A third and related reason for the controversy is that the properties of MSCs change dramatically as they are expanded in culture even if prepared as single-cell–derived clones. There are still no definitive markers for the cells. As a result, the properties of the MSCs prepared in one laboratory differed from those in another, frequently without the investigators being aware of the differences. The problem was highlighted by our recent demonstration that the small, spindle-shaped MSCs present in low-density and early-passage cultures engraft more efficiently than the larger MSCs that appear as the cultures approach confluency.3 

A fourth reason for the controversy is that it is difficult to identify markers to follow engraftment of MSCs as they begin to differentiate in tissues in response to the local microenvironments. Most exogenous labels are fickle in that dye- or iron-based markers can be lost as the cells propagate or are transferred to macrophages and other cells in vivo. Genetic labels such as green fluorescence protein can also generate artifactual results, because the gene products become toxic to cells or generate immune reactions that destroy the cells.

Finally, the controversy has been indirectly fueled by the political controversy over research on human embryonic stem (ES) cells. MSCs can be used as autologous cells and they have little risk of generating tumors that are regularly generated by ES cells. Therefore, there was concern that if MSCs or similar cells from adult tissues engrafted into tissues, the observations could be used as an argument to stop research on human ES cells.

Henschler and colleagues also demonstrated that the binding of human MSCs to human umbilical cord vein endothelial cells (HUVECs) was mediated both by P-selectin and VCAM-1. The rolling and adhesion of the cells was stimulated by TNF-α. In addition, the authors demonstrated that MSCs rolled and adhered to postcapillary venules in vivo in a mouse model in a P-selectin–dependent manner. The observations are a basis for defining the next steps in the engraftment of MSCs—that is, determining whether MSCs extravasate using the same molecular interactions used by other marrow-derived cells. As the authors point out, the results also make it feasible to determine whether the cells can be genetically engineered so that they more effectively home to and engraft into diseased tissues.

The author declares no competing financial interests.

Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells: The International Society for Cellular Therapy position statement.
Pereira RF, Halford KW, O'Hara MD, et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage and lung in irradiated mice.
Proc Natl Acad Sci U S A.
Lee RH, Hsu SC, Munoz J, et al. A subset of human rapidly-self renewing marrow cells (MSCs) preferentially engraft in mice.
Phinney DG, Kopen G, Righter W, Webster S, Tremain N, Prockop DJ. Donor variation in the growth properties and osteogenic potential of human marrow stromal cells.
J Cell Biochem.
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