A number of recent advances in stem cell biology are poised to transform therapeutic approaches to a variety of cardiovascular diseases. In the July issue of the journal Cell Stem Cell, researchers report one such advance, demonstrating that they can direct mouse embryonic stem cells to develop into an embryonic cell layer called the mesoderm, which can differentiate (meaning become different in the process of development) into the heart, blood and other tissues .
Animal embryos differentiate into three cellular layers called germ layers: the ectoderm, mesoderm and endoderm. Tissues and organs of the body develop from these germ layers through further differentiation. The mesoderm germ layer differentiates into circulatory and urogenital systems, connective tissue, muscle and bone.
Embryonic stem cells have the potential to develop into almost any type of cell in the body. To be used therapeutically, however, scientists have to understand how to direct stem cells to become specialized cell types, such as skin or heart cells. Why use stem cells to repair the heart? Heart muscle cells from a patient generally won’t divide in a sufficient number to replace damaged areas. Taking a part of the heart muscle from another area only creates more damage. Embryonic stem cells thus provide an external and abundant source of cells for heart muscle repair.
Scientists at Washington University School of Medicine in St. Louis found that expression of the gene Mesp1 induced expression of mesodermal markers and genetic changes associated with the transition from embryonic to epithelial tissue (termed epithelial-mesenchymal transition).
A typical epithelium is a sheet of cells, often one cell thick, held tightly together by cell-cell junctions in a uniform array. Adhesions between neighboring epithelial cells inhibit movement of individual cells. In contrast, mesenchymal cells have neither organized structure nor tight intracellular adhesion, allowing for increased migratory capacity. Cells undergoing the epithelial-mesenchymal transition (EMT) experience transient structural changes that result in a loss of contact with neighboring cells and a gain in motility. This process is vital to movements that reorganize the embryonic germ layers and to the development of other migratory cell types . Many of the changes associated with cells undergoing developmental EMTs are also observed in wound healing, fibrosis and cancer.
Using mouse embryonic stem cells, researchers showed that Mesp1 expression restricted the potential fates, generating progenitors or precursor cells with the potential to differentiate into cardiovascular cells but, importantly, not into hematopoietic cells (meaning blood-forming cells). They further demonstrated that Mesp1 induces expression of genes specific to cardiovascular development. The authors suggest that Mesp1 may selectively program the development of endothelial, cardiac and smooth muscle cells.
According to senior author Kenneth Murphy, M.D., Ph.D., senior author and Professor of Pathology and Immunology at Washington University School of Medicine :
That’s the challenge to realizing the potential of stem cells. We know some things about how the early embryo develops, but we need to learn a great deal more about how factors like Mesp1 control the roles that stem cells assume.
This work has the potential to one day treat cardiovascular diseases using human stem cells. Scientists next plan to identify gene programs and map out the pathways that specify development of the three cardiac cell types: endothelial, cardiac and smooth muscle cells.
For more information on stem cells and the repair of a damaged heart, see Stem Cell Information at the NIH.
Lindsley et al. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ES cells. Cell Stem Cell, July 3, 2008 DOI: 10.1016/j.stem.2008.04.004
Shook and Keller. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003 Nov;120(11):1351-83.
Gene directs stem cells to build the heart. Washington University in St. Louis Medical News Release. 2008 Jul 2.