Skeletal muscle-derived stem cells may acquire a cardiac phenotype and thus may be a suitable source of cell transplantation to damaged myocardium, according to Chiba University researchers. Skeletal myoblasts have been considered a practical possibility for this purpose, but there has been no clear indication that myoblasts transplanted into a recipient's heart form functional gap junctions with cardiomyocytes and beat synchronously. This study, by Yoshihiro Iijima, investigated whether skeletal muscle-derived stem cells turn to cardiac myocytes and provided some of the evidence that has been lacking.

Primary skeletal myoblasts from leg muscles of GFP-expressed transgenic mice were cultured with cardiac myocytes of neonatal rats. After 5 days, the investigators examined the expression of cardiac-specific proteins (such as cardiac troponin T and ANF). Cardiomyocytes clearly demonstrated these proteins while most GFP-positive skeletal muscle cells did not, however, the fact that a few did express the proteins indicated co-localization of GFP and cardiac-specific proteins. Cardiac transcription factor GATA4, which activates ANF gene expression and is not expressed in skeletal muscle, was also present in skeletal muscle cells.

These findings suggested that the muscle-derived cells changed their phenotype into cardiac myocytes. To determine the mechanism for this change in phenotype, the study examined whether direct contact was necessary. To do so, investigators cultured skeletal muscle cells and cardiomyocytes using a double chamber in which the two types of cells were separated but shared the same medium. Phenotypic change was not demonstrated in this system nor in monoculture conditions, indicating that direct contact is needed for phenotypic change.

Other experiments showed that beating of cardiomyocytes is necessary for phenotypic change, that some GFP-positive cells beat synchronously with neighboring cardiomyocytes, and that cardiomyocyte-like ion channels are expressed in skeletal muscle-derived cells.

The study then identified the potential for phenotypic change among some cell populations of the skin and liver, though not in myoblasts. This yielded the hypothesis that stem cells might be the origin of this change, a concept that was supported by additional experiments in which stem cells were associated, in various ways, with phenotypic change in preparations of skeletal muscle, skin, and liver. The final conclusion was that skeletal muscle-derived stem cells acquire the cardiac phenotype and that tissue-derived stem cells can be the source of cell transplantation.

Adult neural stem cells have the ability to differentiate into vascular cells, not only neural cells. Tufts University investigators, led by Hiromi Nishimura, believe this indicates that vasculogenesis and neurogenesis occur from a common stem cell.

Neural stem cells (NSCs) isolated from adult mouse brain were chosen for study because the clonal growth of neurospheres is well established (each sphere arises from a single cell) and because neurogenesis and angiogenesis share common modulators. In the initial experiment, the NSCs formed ball-like neurospheres, and cells from the neurospheres developed endothelial and smooth muscle phenotypes in vitro, as shown by the expression of VEGF and hypoxia-inducible factor-1 alpha (the core of the neurosphere became hypoxic).

Reverse transcriptase (RT) PCR revealed that large neurospheres expressed hypoxia-related angiogenic growth factors, such as VEGF, angiopoietin 2, and platelet-derived growth factor B chain, more abundantly than small neurospheres.

A variety of lineage markers were demonstrated from experiments involving the NSCs. Neurospheres in a vascular cell-oriented medium stained positively for isolectin B4, a murine endothelial marker, and also expressed smooth muscle lineage markers, such as smooth muscle alpha actin and calponin. Other lineage markers were also expressed in samples isolated from small, large and attached neurospheres. While all samples included some neural and glial markers, early endothelial progenitor markers, and smooth muscle markers, only the attached neurospheres expressed mature endothelial markers and PDGF receptor-type beta.

NSCs can also participate in the regeneration of both vascular and neural tissue following nerve crush injury. Dissociated beta-galactosidase-positive NSCs were administered to mice with unilateral sciatic nerve crush injury; necropsy at 2 weeks disclosed incorporation of beta-galactosidase-positive endothelial cells and vascular smooth muscle cells into foci of robust neovascularization; some neural cells also demonstrated beta-galactosidase. Similar experiments also showed incorporation of endothelial cells and smooth muscle cells into the vascular structure in an ischemic brain model and incorporation of endothelial cells into the neovasculature of an ischemic hindlimb model.

These results indicated that adult NSCs can differentiate into endothelial and smooth muscle lineage as well as neural lineage in vitro and in vivo. In regenerating damaged neural tissue, NSCs may contribute to both neurogenesis and vasculogenesis, resulting in cooperative organogenesis.