Cardiomyogenesis and Neurogenesis

3) Cardiomyogenesis
It has been generally accepted that cardiac myocytes are unable to divide once cell proliferation ceases shortly after birth in the mammalian heart, because mitotic figures have not been detected in myocytes 38). Cardiomyocytes induce DNA synthesis in vivo and in vitro 39, 40). Adult hearts often exhibit a polypoid structure, which results from stochastic accumulation of mutations as cells pass through cell-cycle checkpoints 41). Bone marrow-derived stromal cells (MSC1) are able to differentiate into cardiomyocytes in vitro and in vivo 19, 20, 42, 43) and a hierarchical model has been proposed for this in vitro cardiomyogenic differentiation. MSC1 in culture include a mixture of at least three types of cells, i.e., cardiac myoblasts, cardiac progenitors and multi-potential stem cells, and a follow-up study of individual cells suggests that commitment of a single-cell-derived stem cell toward a cardiac lineage is stochastic 44). Furthermore, MSC1 over-expressing well-known master transcription factors, i.e., Csx/Nkx2.5 and GATA4, unavoidably undergo cardiomyogenic fate and behave like transient amplifying cells. MSC1 also transdifferentiate into cardiomyocytes in response to humoral factors, such as demethylation of the genome, in addition to environmental factors (See the chapter “Epigenetic modifier as a differentiating inducer”.

4) Neurogenesis
MSC1 can exhibit neural differentiation when exposed to demethylating agents 14): the cells differentiating into three types of neural cells, i.e., neurons, astrocytes, and oligodendrocytes. With exposure to basic fibroblast growth factor, nerve growth factor, and brain-derived neurotrophic factor, the transdifferentiation of human stromal cells is limited to neurons 14). The change in gene expression during differentiation is global and drastic 45): the differentiated cells no longer exhibit the profile of mesenchymal cells or the biphenotypic pattern of neuronal and mesenchymal cells. Osteoblasts capable of intra-membranous ossification are likely to differentiate into neuronal lineages, but adipocytes do not 14). Interestingly, the cranio-facial membranous bones develop from the neural crest, which is of ectodermal origin. Development naturally progresses from neural crest cells to terminally-differentiated osteoblasts 46). The finding of in vitro differentiation from mesoderm- to ectoderm-derived cells is thus the opposite of the developmental process, i.e., from ectoderm- to mesoderm-derived cells. Converting differentiated osteoblasts or MSC1 to neuronal cells, a key future task for any cell-based therapy, would thus oppose the usual direction of cell differentiation. This can now be achieved by exposing stromal cells to neurotrophic factors, at least in vitro.
Dopaminergic neuron-associated genes, such as nurr1 and wnt-5a, are induced at an extremely high level in the neuronally-differentiated stromal cells. Wnt5a and nurr1 are involved in the differentiation of mid-brain precursors into dopaminergic neurons 25, 26). It is quite significant that dopaminergic neurons can be generated from MSC1, since they are one of the key targets for regenerative medicine.