Nick Wright : Histopathology

Goals

Previous and current research

We have identified several gut reparative cell lineages, and shown that they produce a number of novel molecules which stimulate the growth and migration of gut epithelial cells. We are also interested in the earliest phases of colorectal and gastric cancer, and are defining the first morphological and genetic changes in these common diseases. The origin of cell lineages from stem cells in the intestine is also being examined using in vitro and in vivo models we have developed.

We have also shown that bone marrow stem cells contribute to hepatocytes in humans, into pericryptal myofibroblasts in the intestine, and also into tubular epithelium in both animals and man. We have demonstrated that bone marrow cells contribute significantly to keratinocytes in the epidermis and hair follicle, and also to fibroblasts and myofibroblasts in normal and healing tissues, including the stroma of animal and human tumours and liver scarring in cirrhosis. We have also found that entire new vessels - 'neovasculogenesis' - can form from bone marrow cells in inflammatory conditions in the adult intestine - previously only seen in the embryo. We have shown that such bone marrow cell lineages proliferate in situ. We have also successfully used lentovirally-transfected bone marrow stem cells to correct haemophilia in an experimental mouse model.

Future projects

We will examine the factors which determine bone marrow stem cell homing and transformation in vivo. That liver and kidney cells can derive from marrow opens up several therapeutic options: replacement of lost parenchyma, correction of single gene defects and the delivery of molecules such as cytokines to the liver, as we showed in haemophiliac mice.

In the liver, our model is the hepatitis B surface antigen positive transgenic mouse, which develops chronic hepatitis and liver cancer. Targeting of bone marrow cells bearing interferon genes could colonise the liver with resistant hepatocytes. We also use several models of kidney and intestinal damage to study bone marrow stem cell engraftment, repair and regeneration. We will explore the mechanisms of bone marrow-derived vasculogenesis and how renal tubular cells are formed from bone marrow and clonally proliferate.

Our work on gut cancer explores how intestinal crypts are colonised by mutated stem cells, and uses mitochondrial (mDNA) and genomic DNA mutations to map intracryptal spread of mutated stem cells. We champion the view that colonic adenomas grow by crypt fission, and are using mDNA mutations to examine clonal growth by fission, and the role of Wnt signalling. We also study the role of nutrients in gut growth control, and the effects of angiogenesis inhibitors on the development of gut tumours.