George Daley's lab focuses on stem cell biology, with an emphasis on somatic cell reprogramming, hematopoietic differentiation from human and mouse pluripotent stem cells, and common mechanisms in reprogramming and cancer. His laboratory has pioneered the study of murine and human cell culture models of leukemia and genetic bone marrow disease and the role of the Lin28/let-7 pathway in human cancer and metabolic disease.
Role of Lin28 and its microRNA target let-7 in cancer progression and metastasis
Lin 28 gene products are RNA-binding proteins that are normally expressed during embryogenesis and only in restricted tissues past mid-gestation. Lin28A and Lin28B are closely related paralogs that play roles in early development, reprogramming to pluripotency, and tumorigenesis. Much of the characterization of these proteins have focused on their interaction with the tumor suppressor miRNA, let-7. We will investigate the translational regulation of Lin28A and Lin28B specifically in neuroectodermal and endodermal lineage cells and their malignant counterparts specifically lung and melanoma. Furthermore, we will use embryonic stem cells, iPS cells, and a few Lin28-induced cancer models to dissect how Lin28a and Lin28b regulate cellular metabolism through binding to their mRNA and microRNA targets, and how this tightly regulated metabolic program contribute to stemness and tumorigenesis.
Use of embryonic and induced-pluripotent stem cells for hematopoietic cell generation
Transplantation of hematopoietic stem cells (HSCs) can be curative for a variety of malignant and genetic blood diseases, but the lack of matched donors and transplant-related complications limits wider application. One strategy is the creation of autologous-HSCs via cellular reprogramming, as it is now feasible to generate induced-pluripotent stem cells (iPSCs) from virtually any patient, and to repair gene defects via genome editing. Furthermore, we have shown that human iPSC-derived blood precursors can be converted (or respecified) into transplantable multilineage progenitors. Respecified iPSC progenitors are a particularly potent source of red blood cells in vitro and in vivo. Thus, we will use iPSC lines from patients with congenital anemias to create in vivo models of these disorders to interrogate the underlying disease mechanisms and as platforms for drug testing.