Mechanisms of differentiation. The 4 models shown represent mechanisms of differentiation from BM-derived cells into an alternative nonhematopoietic phenotype (green). (A) Consistent with our existing paradigm that cells always travel from a less differentiated to a more differentiated state, this model predicts that there is a highly pluripotent cell (red) that has not yet committed to the hematopoietic lineage and maintains the ability to differentiate into multiple diverse cell types. (B) With indirect transdifferentiation, an HSC changes its gene expression pattern to that of an alternative cell type through a dedifferentiation/redifferentiation pathway that presumably passes through an as yet unidentified intermediate cell type, shown in white. (C) In direct transdifferentiation, an HSC may be able to directly change its gene expression pattern from that of a hematopoietic stem cell to an alternative cell type. (D) If fusion is the mechanism by which BMSCs acquire a nonhematopoietic phenotype, a marrow-derived cell, perhaps a macrophage (blue), fuses with a nonhematopoietic cell (yellow), and the nucleus of the marrow-derived cell takes on the gene expression pattern of the nonhematopoietic cell type. The 2 nuclei do not have to fuse. Note that these models are not mutually exclusive and may all reflect the in vivo mechanisms involved. These models apply equally well to MSCs and MAPCs, which may directly transdifferentiate into multiple cell types, dedifferentiate through an intermediate cell type, represent highly pluripotent stem cells with the ability to differentiate directly into multiple cells types, or have the ability to fuse with different cell types.