We are currently developing a number of novel approaches aimed at differentiation of embryonic stem (ES) cells into mature and functional hepatocytes and pancreatic beta (insulin-producing) cells. We are also focusing on the differentiation of embryonic neural progenitor cells into neurons and glial cells. In addition, we are working on developing therapeutic uses for bone marrow-derived mesenchymal stem cells (MSCs).

One of the major hurdles of cellular therapies for the treatment of liver failure is the limited availability of functional human hepatocytes. While ES cells represent a potential cell source for therapy, current methods for differentiation result in mixed cell populations or low yields of the cells of interest. Our objective is to develop a rapid, direct differentiation method that yields a homogeneous population of hepatocyte-like cells. We use a variety of techniques, including ES cell microencapsulation, delivery of growth factors using microfabricated flow chambers, coculture with primary adult hepatocytes, and induction of metabolic machinery that accompanies differentiation. Our results show that we can successfully proliferate and differentiate ES cells into a uniform and homogeneous population of hepatocyte-like cells that possess hepatic morphology, functionality, and gene and protein expression.

In the area of pancreatic beta cells, we are evaluating the effects of culture medium composition, extracellular matrix configurations, and coculture with primary hepatocytes on the differentiation of ES cells into insulin-producing cells. Our work on neural stem cells focuses on controlling the fate of radial glial cells using localized sources of secreted factors. Gradients of secreted factors are generated using microfluidic devices.

Our work using bone marrow-derived MSCs is based on the fact that they have the ability to inhibit the proliferation and/or differentiation of specific immune cells to activating stimuli. We are developing a MSC-based extracorporeal bioreactor that exploits MSC-derived factors for use in inflammatory conditions. Based on our expertise, we are using an animal model of fulminant hepatic failure (FHF), which has a critical inflammatory component, as an in vivo test bed for device efficacy. Recent in vivo testing of our MSC-based extracorporeal bioreactor has demonstrated a significant survival benefit in treating FHF.