Defining the role of the bone marrow vascular niche in hematopoiesis
The Chute Lab has utilized complementary approaches, including engineered mice, bone marrow transplantation models, high-resolution microscopy and pharmacologic interventions to define the role of bone marrow endothelial cells in regulating hematopoietic stem cell regeneration following medically relevant injury from chemotherapy or irradiation. The results of these studies shifted the paradigm of understanding of the role of the bone marrow microenvironment, or niche, in regulating hematopoietic stem cell regeneration in adults.
Discovery of niche-derived paracrine factors that govern hematopoietic regeneration
The bone marrow niche provides essential signals that control hematopoietic stem cell maintenance, self-renewal and regeneration, but many of these niche-derived mechanisms remain unknown. Utilizing a combination of high-throughput RNA sequencing, proteomics and cell-specific engineering techniques, the Chute Lab has discovered and characterized several niche-derived proteins, including pleiotrophin, DKK1 and epidermal growth factor that have an essential role in regulating hematopoietic stem cell regeneration following myelosuppression.
Discovery of the role of protein tyrosine phosphatase receptors in controlling hematopoietic stem cell regeneration
Transmembrane protein tyrosine phosphatase receptors provide counterbalance to receptor tyrosine kinases in regulating cellular activation. The Chute Lab discovered that mouse and human hematopoietic stem cells are highly enriched for expression of protein tyrosine phosphatase sigma, and genetic or pharmacologic inhibition of protein tyrosine phosphatase sigma causes a marked expansion of hematopoietic stem cells in vivo. We have also partnered with experts in medicinal chemistry to develop lead compound small molecules that powerfully inhibit protein tyrosine phosphatase sigma, and accelerate mouse and human hematopoietic recovery in vivo as a model for clinical application.