We are studying the regulation of hematopoietic stem cells in order to understand how signaling pathways, transcriptional mechanisms and epigenetic regulators govern stem cell behavior to determine stem cell fate options. Integrative signaling and transcriptional networks act in concert to determine whether hematopoietic stem cells remain quiescent, proliferate and self-renew, expand through self-renewal, differentiate or undergo apoptosis. We study various regulators in health and disease to determine how we can i) expand stem cells in vivo and ex vivo ii) understand the pathogenesis of blood malignancies and genetic disorders of the blood system and iii) develop cell and gene therapies for these disorders.
Value of research
Stem cell therapy is a growing therapeutic modality for serious genetic disorders and malignancies because of the difficulties in treating these diseases with conventional small molecule pharmaceuticals. Although increasing knowledge about the regulatory pathways that govern stem cell fate may lead to the discovery of small molecule drugs that can be used to expand stem cells or treat leukemia, the main therapy that is currently working in the clinic to treat serious blood disorders is blood and marrow transplantation (BMT). BMT has been used in the clinic for decades and is therefore paradigmatic for other stem cell therapies to provide a spearhead for development. The most frequent candidate diseases for BMT are malignant blood disorders, particularly leukemia and lymphoma.
Traditionally, bone marrow cells were the leading source of donor cells for BMT but in recent years peripheral blood stem cell transplants have become more common and since 1989, transplantations using umbilical cord blood (CB) donor cells have been increasing greatly, particularly in children. CB has many advantages as a donor cell source in BMT, such as the wide availability of CB (banked cryopreserved cord blood), reduced frequency and severity of graft versus host disease (GVHD) and faster availability of the donor cells which is particularly important for the treatment of acute leukemias. However, a disadvantage with CB is the limited number of hematopoietic stem cells (HSC) and progenitor cells in each CB sample. While the number of HSC and progenitors is not a problem in pediatric transplants it can be problematic to get efficient and fast engraftment in adults due to the limited number of repopulating long-term and short-term HSC and an adequate number of hematopoietic progenitors. Since a large majority of transplant recipients are adults, it would be very beneficial to be able to increase the number of HSC in the banked CB samples.
Expansion of cord blood stem- and progenitor cells in liquid culture media represents an approach to increase the number of cord blood stem cells and to promote hematopoietic engraftment. The development of reliable methods that can expand the number of HSC 2-3 fold would make most CB samples suitable for BMT therapy of adult patients. Development of expansion of autologous hematopoietic cells can also be used to increase gene transfer efficiency and improve engraftment of genetically modified stem cells in clinical gene therapy for blood disorders
- Understand the regulation of hematopoietic stem and progenitor cells by studying known signaling pathways and by discovering novel stem cell regulators.
- Develop methods to expand hematopoietic stem cells and early progenitors ex vivo and in vivo to improve engraftment following blood and marrow transplantation.
- Understand the pathogenesis of Diamond Blackfan anemia and develop mechanism-based therapies for this disorder, including gene therapy.
- Develop curative gene therapy for the most common lysosomal storage disorder, Gaucher disease, a disease that affects mostly macrophages.