Stem Cell Biology & Gene Therapy: Mostoslavsky Lab
Basic Science Research
Gustavo Mostoslavsky MD PhD
Welcome to the Mostoslavsky Lab!
The Mostoslavsky Lab is a basic science laboratory in the Section of Gastroenterology in the Department of Medicine at Boston University, affiliated with the Boston University Center for Regenerative Medicine (CReM). Our goal is to advance our understanding of stem cell biology with a focus on their genetic manipulation via gene transfer and their potential use for stem cell-based therapy. We believe that by discovering the mechanisms involved in stem cell self-renewal and differentiation we will be able to manipulate stem cell fate and use it as the basis for the correction of several diseases. Project areas in the lab focuses on the use of different stem cell populations, including embryonic stem cells, induced Pluripotent Stem (iPS) cells, hematopoietic stem cells and intestinal stem cells and their genetic manipulation by lentiviral vectors.
Specific Areas of Research
Embryonic Stem Cell Modeling of Intestinal Differentiation
Embryonic Stem Cells (ESC) are pluripotent undifferentiated cells capable of giving rise to cells from all three germ layers. This unique ability makes them ideal candidates to model early development allowing us to study the basic signaling mechanisms involved in stem cell fate determination. At the same time, manipulating ESC differentiation toward a specific developmental pathway holds a great promise for their use in regenerative medicine. One focus of our lab is differentiating mouse ESC into intestinal epithelial cells in order to understand the complex signaling pathways involved in intestinal commitment from endodermal progenitors and undifferentiated stem cells.
Our lab has a major interest in the study of induced Pluripotent Stem cells or iPS cells and the development of tools for their generation and characterization. Pioneering work by the laboratory of Dr. Yamanaka showed that fibroblasts transduced with retroviral vectors expressing four transcription factors, Oct4, Klf4, Sox2 and cMyc can be reprogrammed to become pluripotent stem cells that appear almost indistinguishable from ESC. In contrast to ESC, iPS cells are genetically identical to the individual from whom they are derived, raising the prospect of utilizing iPS cells for autologous cell based therapies without risk of rejection. We have previously developed a single lentiviral vector expressing a stem cell cassette, named STEMCCA, capable of generating iPS cells from post-natal fibroblasts with the highest efficiency reported to date. We have recently modified it to make it excisable and have used it to generate mouse and human iPS cells free of exogenous transgenes. We aimed at using iPS cells in parallel to ESC for the study of endoderm/intestinal lineage specification, as well as for disease modeling and their potential for regenerative medicine. We are currently establishing and characterizing iPSC lines from several GI tract related diseases, including Familial Adenomatous Polyposis (FAP), Crohn’s disease and Hemochromatosis.
Hematopoietic Stem Cell Manipulation for the Study of Stem Cell Self-Renewal and Differentiation
Hematopoietic Stem Cells (HSCs) are the most thoroughly characterized stem cell population in the body and their study has resulted in well established methods for their isolation, purification and reliable assays of HSC function. During the last few years we have substantially improved our ability to genetically manipulate HSCs using viral vectors for gene transfer. Despite these efforts, few genes are known to play a role in the processes of stem cell self-renewal and differentiation. Understanding the molecular mechanisms that govern those unique functions are crucial for developing the promise that stem cells hold for developmental biology and regenerative medicine. In our lab, we use lentiviral viral gene transfer to study the role of several molecules in long-term HSC self-renewal and differentiation.