Time to end the stem cell wars?

Comment on Kawada et al, page 3581

Kawada and colleagues demonstrate that MSCs from bone marrow become cardiomyocytes in infarcted mouse hearts. The results address a raging controversy about stem cells.

Several prominent scientists have maintained that the only true stem cells in bone marrow are hematopoietic stem cells (HSCs) and that HSCs do not have any potential to differentiate in nonhematopoietic tissues.¹  Several recent reports in high-profile journals appear to demonstrate conclusively that donor cells are not found in nonhematopoietic tissues after infusions of labeled bone marrow or HSCs or in experiments with parabiotic animals. As an alternative argument, several scientists have concluded that the apparent plasticity of mesenchymal stem cells (MSCs) and similar stemlike cells can be completely explained by cell fusion.

In contrast, the report by Kawada and colleagues is consistent with observations initially made over 30 years ago and now extensively confirmed and extended.^2,3  In their review of earlier work done by Friedenstein and colleagues, Owen and Friedenstein²  report that the few plastic-adherent cells found in bone marrow (MSCs) can differentiate into multiple cell phenotypes both in culture and in vivo. The cells readily generate clones and the clones are multipotential for differentiation in culture under conditions that obviously exclude cell fusion. Several subpopulations of stemlike cells from marrow and other tissues, whose multipotentiality for differentiation is the same as or perhaps even greater than that of MSCs, have now been identified. In addition, numerous reports have demonstrated that MSCs or similar cells from marrow can differentiate into nonhematopoietic cells both in animal experiments and in patients. A few preliminary trials with MSCs in patients have shown promising results.³ FIG1 

Why then the controversy? The answer lies, in part, in the complexity of the biology. It begins with the difficulty of precisely defining a stem cell. The CD34 epitope has been extremely important for identifying HSCs, but we now know that HSCs can undergo reversible changes from CD34⁺ to CD34^– states. Even differences in cell cycle can alter the efficiency of engraftment of HSCs. In the case of MSCs, the cells demonstrate dramatic changes in their properties during expansion in culture and the changes are reversible through several passages. This chameleon-like nature of stem cells is likely to explain some negative results. A second level of complexity lies in the limited animal models that are available for testing engraftment into nonhematopoietic tissues. In adult animals, the level of engraftment of MSCs into intact tissues is frequently less than 0.01%. Therefore, it is relatively easy to do a negative experiment with assays that are not sufficiently sensitive or with cell markers that are fickle when used in vivo. Higher levels of engraftment are seen with injury to tissues, as indicated by Kawada et al and many other reports. However, induced injuries are not all the same in terms of the severity, and they probably are very different in the signals they release to attract stem cells. Moreover, current data suggest that stem cells from marrow are not mobilized until similar reparative stemlike cells found in most tissues are exhausted. These variables again confound the interpretation of negative data. Cell fusion by stem cells has been found to be a more frequent event than previously recognized, but a current hypothesis is that cell fusion followed by reductive division may be a rapid mechanism of tissue repair. Clearly, we are still early in our understanding of how stem cells can repair tissues and of how we can make them more effective.

But why is the current controversy so strident? One answer is found in the frequent inquiries that those of us who work with adult stem cells receive from religious and political leaders asking, “Is research with human embryonic stem cells still necessary?” Obviously it is, but we will all lose if our defense of research on embryonic stem cells distorts the scientific debate about adult stem cells. Another answer to why the controversy is so strident lies in the fact that the stakes are very high. With millions of patients looking over our shoulders, we are obliged to sort out as carefully as we can both the negative and the positive observations.