Development and bioengineering of the thymic microenvironment
A long-standing question for the Crooks research program is how human lymphoid commitment is controlled, both by intrinsic transcriptional networks during differentiation from hematopoietic stem cells, and by the microenvironment of the bone marrow and the thymus. The thymus is necessary for the generation of T cells from hematopoietic stem cells and lymphoid progenitors. Thymic function deteriorates with aging and also after chemotherapy, stem cell transplantation, irradiation and infections such as HIV. Poor thymic function can increase the risk of infection, autoimmune diseases and cancer. Our group has studied the microenvironment of the neonatal thymus, stimulated by our observations in both in clinical stem cell transplantation and in experimental models that reconstitution of the thymus during early postnatal life is qualitatively different to that in later childhood. Through our investigations into those mechanisms that drive thymic growth in the neonate, we have developed the tools to characterize the rare murine and human thymic stromal sub-populations present during embryonic and postnatal development, using flow cytometry and gene expression profiling. Using the knowledge gained from these basic studies we are building an understanding of the cross-talk that exists between mesenchymal and epithelial cells in the thymus and how it changes during times of growth and involution.
In closely related studies, we have recently developed surgically implantable thymic organoids, generated from cultured and expanded postnatal human thymic epithelium and mesenchyme. These thymic organoids can be genetically manipulated and can generate T cells from human or mouse HSC in vivo (Chung et al, Stem Cells 2014). We are now developing bioengineering and culture methods to clinically translate this technology.