Induction of hematopoietic cell fate from neuronal and muscle cells in the human

Recent studies in the mouse have demonstrated that cells isolated from adult brain or muscle are capable of hematopoietic function. These studies suggest that the functional potential of stem cells is not restricted to the tissue source from which they are derived, thereby challenging fundamental concepts of stem cell biology. The ability for cells of one tissue to produce cells of another tissue has been operationally defined as cellular 'plasticity'. In addition to the intellectual significance of these findings, the utility of stem cell plasticity in cell replacement therapy is unlimited. However, this exciting therapeutic potential of stem cell plasticity is exclusively predicated from experimental evidence in the mouse, and it remains unknown if human cells are capable of similar function. Here, hematopoietic capacity of human brain and skeletal muscle was examined before and after culture in a variety of conditions. Ex vivo culture with chick embyronic extract (CEE) promoted the survival of both neural and muscle cell types, but was unable to demonstrate the formation of human hematopoietic progenitors. However, addition of BMP-4 and EPO promoted hematopoietic cell fate and multilineage hematopoietic progenitor expansion. Rare subfractions of de novo isolated muscle and neural cells were shown to express cell surface AC 133 and CD34, however, AC 133 expression was lost after ex vivo culture in CEE while BMP-4 and EPO promoted AC 133 and CD34 expression. Neither neuronal nor muscle cells were able to repopulate the bone marrow of immunodeficient murine hosts, however human chimerism was observed at high frequencies in the muscle, lung and spleen. Our data suggests that hematopoietic capacity can be detected in human neural and muscle tissue, and that BMP-4 and EPO signaling is critical to this process. We suggest that the origin of hematopoiesis from these tissues may arise from novel hematopoietic progenitors resident in these tissue sites, or alternatively may be due to cell fate switching. Further comparison of hematopoietic progenitors derived from human fetal blood to those derived from muscle and neural tissue will allow us to characterize the nature and mechanisms responsible for hematopoietic potentials in the human.