Pilot Project

Ronald Hoffman
Ronald Hoffman, MD
Professor Medicine, Hematology and Medical Oncology
Professor Gene and Cell Medicine
Mount Sinai School of Medicine

The use of Recombinant Human Acid Ceramidase for ex vivi Hematopoietic Stem Cell Expansion

The clinical use of hematopoietic stem cells (HSCs) is limited by our inability to successfully expand this population of cells in culture. Significantly improved ex vivo expansion of HSCs could theoretically provide a source of cells for bone marrow transplants, stem cell based gene therapy, and red blood cell transfusions, while reducing the risk of transfusion related infection. While we know that this population of cells has the potential to dramatically expand while maintaining its pluripotent potential, as evident by the small population of HSCs required to reconstitute an individual's entire hematopoietic system in postablative bone marrow transplants in humans, a method to expand HSCs to a clinically meaningful quantity in the laboratory has yet to be developed. We hypothesize that we may enhance our ability to expand HSCs ex vivo through manipulating the sphingolipid pathway. Over the last two decades thousands of papers have revealed that, in response to a variety of stimuli, the sphingolipid pathway has a major role in determining the cell fate of a large and diverse group of cell types, including HSCs. Specifically, stress induced ceramide generation is known to mediate cell death, senescence, and differentiation. The ceramide metabolizing enzyme, acid ceramidase (AC) serves as a rheostat between ceramide and the anti-apoptotic, pro-proliferative lipid, sphingosine-1-phosphate (S1P). As such, experiments planned with exogenous recombinant human AC (rAC) may uncover a novel and important strategy that has the potential to dramatically enhance the expansion of HSCs.