Medical Professional Publications

Regulating the Fate of Mesenchymal Stem Cells, Attractive Candidates for Repairing and Engineering Blood Vessels to Treat Ischemic Diseases

Dr. Brenda Lilly, principal investigator(From the July 2014 Research Now)

Bone-marrow derived stem cells called mesenchymal stem cells, or MSCs, have the potential to differentiate into unique cell types under defined conditions. MSCs also play an important role in stimulating the process of new blood vessel formation, making them attractive candidates for tissue engineering and organ repair. A new study, led by a team in The Research Institute at Nationwide Children’s Hospital and published in Stem Cells and Development in June, provides insight into the vascular conditions that cause mesenchymal stem cells to become smooth muscle cells.

MSCs can give rise to many, but not all, types of cells in the body, including endothelial cells and smooth muscle cells, the two primary cell types that comprise a functional blood vessel. The formation of new blood vessels from MSCs could greatly benefit patients with ischemic injuries, such as stroke and myocardial infarction.

“Understanding how MSCs act in the context of other cells is fundamental to understanding how they differentiate into other cell types,” says Brenda Lilly, PhD, senior author of the study and a principal investigator in the Center for Cardiovascular and Pulmonary Research at Nationwide Children’s. “Endothelial cells are a major cell type that is essential for blood vessel formation. The signals they send and receive are critical.”

Dr. Lilly and Cho-Hau Lin, MS, a graduate student researcher at Nationwide Children’s, demonstrated that endothelial cells direct MSCs toward a smooth muscle cell fate, and that a cellular pathway known as Notch signaling is essential for this differentiation process. Notch signaling is one of three mechanisms that have been implicated in regulating MSC differentiation and in regulating the recruitment and differentiation of vascular smooth muscle cells by endothelial cells.

“The findings from this study clearly indicate the importance of the cellular environment on mesenchymal stem cell differentiation,” says Dr. Lilly. “Understanding the potentially critical role that endothelial cells have deciding the fate of mesenchymal stem cell may also have significant clinical implications for cell-based treatments for patients with ischemic diseases.”

Data from prior studies have established that endothelial cells impact the function of vascular smooth muscle cells by regulating how they contract. In particular, endothelial cells secrete endothelin, a protein that increases blood pressure and vascular tone, which may be beneficial in the treatment of cardiac and vascular diseases.

To better understand what changes specifically occur in the vascular environment for MSCs to become smooth muscle cells, Dr. Lilly and her team examined the effect that co-cultured endothelial cells had on the gene expression and function of contractile genes and stem cell markers — the genes and protein products that characterize various stem cell populations.

“It is well-established that endothelial cells impact vascular smooth muscle cell function by governing their contractile response,” says Dr. Lilly.  “Data from our study showed that endothelial cells cause an increase in contractile gene expression, while also decreasing stem cell markers. Additional analyses also indicated that endothelial cells promote a unique smooth muscle phenotype that may contribute to blood vessel formation.”

The ability of endothelial cells to induce MSC differentiation toward a smooth muscle cell fate is separate and distinct from previously described differentiation processes, she says. This study highlights the importance of considering both the vascular environment and the endothelial cell-environment when manipulating the fate of MSCs to engineer and repair blood vessels as treatments for ischemic diseases.

Full citation:
Lin CH, Lilly B. Endothelial cells direct mesenchymal stem cells toward a smooth muscle cell fate. Stem Cells and Development. 2014 Jun 10. [Epub ahead of print].

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