The mechanisms for SC-mediated differentiation events, including documented functional recovery, are still under considerable scientific debate. For adult SCs, the controversy between transdifferentiation and fusion has still to be solved. Recently, it was reported that BMSCs are able to “transdifferentiate” or change commitment into cells that express early heart, skeletal muscle, neural, or liver cell markers.56- 59,64 Similarly, SCs from the BM contributed to the regeneration of infarcted myocardium.68,69 This was supported by the observations in humans that transplantation of SCs from mobilized peripheral blood expressing the early hematopoietic CD34+ antigen led to the appearance of donor-derived hepatocytes, epithelial cells, and neurons.70 Therefore, it was initially presumed the repair seen in damaged host tissues following SC transplantation or homing was due to incorporation and transdifferentiation of the BMSCs at the sites of damage. However, a number of studies have challenged this concept, providing evidence that BMSCs may instead incorporate into host tissues via fusion with host cells.71,72 One of the key studies demonstrating evidence for fusion was that of Alvarez-Dolado et al,73 where they examined CD45+ BMSCs and found that essentially all integration of these cells into host tissues involved fusion. Because the CD45+ subset of BM-derived cells is now thought to be committed to the hematopoietic lineage (as opposed to CD45− cells, which give rise to other nonhematopoietic lineages), one could argue that Alvarez-Dolado et al did not examine the appropriate subset of cells capable of contributing to nonhematopoietic tissues. Additionally, they only examined incorporation of CD45+ cells into normal tissues, as opposed to sites of damage, where the mechanism of integration may be different because of the inflammatory milieu. Nevertheless, other studies have also found evidence that SCs can fuse with host cells, forming heterokaryons.71 Such studies raise the question as to whether the transdifferentiation of BMSCs seen in culture really occurs when these cells are injected in vivo or whether their primary therapeutic contribution is instead via fusion with host cells. Other reports found no proof of host cell fusion when SCs differentiate in the host.74 Further, there is evidence that a single BMSC can repopulate the BM, giving rise to all hematopoietic precursors, and that such cells could in turn contribute to other nonhematopoietic tissues. The question of fusion with host cells vs transdifferentiation in vivo is the topic of several comprehensive reviews and reports that conclude that definitive experiments on this topic are lacking.75,76 Therefore, it remains unresolved as to whether BMSCs integrating into damaged tissues undergo transdifferentiation in vivo to express markers of differentiation or whether they express such markers as a result of fusion with endogenous host cells.