Liver regeneration is critical for health. We focus on cell-based therapies and translational aspects of stem cell biology for regenerating liver. Major efforts are devoted to understanding cellular and molecular mechanisms that impair proliferation of native cells in health and disease. Mechanisms are examined by which cell transplantation may advance liver regeneration. This includes how transplanted cells may engraft, proliferate and function in liver. Cell interactions that may benefit liver regeneration are of interest. The therapeutic potential of liver cell types is also of interest. We define molecular aspects of hepatic differentiation in human stem/progenitor cells isolated from tissues or hepatocytes generated by differentiation of pluripotent stem cells. Comparative analysis of such cells is of interest for mechanisms in gene regulation. Expression of therapeutic constructs and transplantation of those cells is another area of investigative interest. In other projects, we determine whether endogenous stem/progenitor cells may be activated by cell therapy approaches. This concerns identification of specific paracrine factors released by transplanted cells. This interfaces with opportunities for candidate drug development for modulating receptors with cytoprotective potential. Intracellular signaling pathways and mechanisms related to DNA damage and repair, as well as mitochondrial biology have become relevant. Diseases of therapeutic interest include acute liver failure (mechanisms for liver regeneration), genetic deficiency states (Wilson's disease with hepatic copper toxicosis for cell/gene therapy approaches), and coagulopathies (disease correction with cell therapy). Tissue engineering to generate neo-liver has potential in these areas and is studied in experimental models.
Microarray or deep sequencing-based methods are routinely applied for gene expression. Established cell and molecular biology methods are broadly used. Several rodent models are used, including hemophilia A mouse, Gunn rat, Nagase analbuminemic rat, dipeptidyl peptidase IV deficient (DPPIV-) rat and DPPIV- mouse, Long-Evans Cinnamon rat, etc. Animal models with induced acute or chronic liver injury are available. The DPPIV- rat and mouse-based transplantation systems have been helpful for fate of transplanted cells. Cell culture assays are used for mechanistic analyses. Studies are also devoted to major issues in transplantation, e.g., cryopreservation, organ donor expansions through study of nonheart-beating donors. Clinically used drugs are used to advance translation.
We collaborate with leading investigators at Einstein or elsewhere as indicated.