The broad interest of the WAGERS LAB is to identify and analyze tissue-specific stem cell populations in adult animals. This work focuses on understanding the factors controlling the migration and expansion of bone marrow-derived and blood-forming (hematopoietic) stem cells in mice, as well as developing methods for the isolation and manipulation of distinct stem and progenitor cell populations from adult mouse skeletal muscle.

Every year, tens of thousands of patients undergo bone marrow or peripheral blood progenitor cell transplantation for the treatment of diverse diseases (including leukemia, lymphoma, immunodeficiency and others). The success of these transplants depends critically on the surprising ability of intravenously infused hematopoietic stem cells, which normally reside predominantly in the bone marrow, to accurately and efficiently migrate from the blood to the marrow of transplant recipients, whose own blood system has been compromised by radiation and/or chemotherapy. Once there, these stem cells are further required to expand and differentiate to repopulate all of mature cells in the patient's blood. Importantly, failure or inefficiency in any one of these stages of transplantation can cause failure of the stem cell graft, and so, understanding the molecular and cellular processes that permit these stem cell functions is essential for improving transplant outcomes. To this end, we are pursuing both genetic and cell biological approaches to defining genes and gene products that control stem cell migration, expansion, differentiation and survival, in order to devise better engraftment strategies that limit transplant-associated complications. In addition, in collaboration with an NIH-funded consortium of investigators interested in applying stem cell transplant-based therapeutics to the treatment of single gene disorders, we also are developing new, robust approaches for precise and directed gene-modification of stem cells, to support the effective use of gene-corrected stem cells for the treatment of sickle cell disease and related disorders.

Currently, blood-forming stem cells are the only adult stem cell population that has been purified and used for the treatment of human disease. To develop equally robust cell therapies for treating non-blood-cell-related disease, cells with equivalent regenerative function for non-blood tissues must be identified. To this end, we have developed cell surface marker based approaches to directly identify and isolate lineage-specific precursor cells in adult skeletal muscle. These precursors include cells with robust muscle-forming activity, which when transplanted into animals with injured or defective skeletal musculature, are able to reconstitute both muscle fibers and regenerative satellite cells, improving muscle function and providing enduring muscle regenerative function. Our ongoing studies are aimed at further defining cell lineage relationships in the differentiation of muscle stem and progenitor cells, enhancing the efficiency with which these cells can be transplanted and regenerate skeletal muscle, as well as identifying signaling pathways and gene expression programs important for maintaining the regenerative potential of these muscle-resident stem cells throughout life and preventing their malignant transformation in the context of myogenic sarcomas.