Niche oncogenesis

Published on March 5, 2014   35 min

Other Talks in the Series: Stem Cells

This is David Scadden. I'm hematologist-oncologist at Mass General Hospital, co-direct the Harvard Stem Cell Institute, and co-chair of the Department of Stem Cell and Regenerative Biology at Harvard University. I'll be talking today about niche oncogenesis, the role of the hematopoietic stem cell niche in particular, and the development of malignancy.
The stem cell niche is a concept first proposed by Ray Schofield back in 1978 when he was looking at blood stem cells. At the time, the method by which cells were analyzed was called a colony-forming unit of the spleen-- a so-called CFU-S. And he recognized that stem cells that he had been able to isolate from the spleen in these colonies seemed to behave less robustly than stem cells derived from the bone marrow. And he proposed what now seems to be an entirely obvious concept, that where a stem cell resides was in some ways playing a critical role for its function-- that the niche was the basis for stem cells having regulated self-renewal and differentiation. It was a competing hypothesis at the time, which was that stem cells had their own intrinsic engineering and were capable of going in the direction that they knew best. And it was Ray Schofield who proposed that there was this imposition of information from the tissue in which the stem cell resided. It was a concept initially, and one that really did not have much in the way of experimental definition until some years later and mostly in invertebrates.
So the ability to then use this information as a way to try to understand and experimentally define how stem cells behaved in vivo in mammalian systems was first tested in the hematopoietic system. And their, my lab and other labs were interested in just what the relationship was between bone marrow and the bone in which bone marrow resides, and hypothesized that there might be something regulatory about bone that governed stem cell function. And so we set out to initially just look at models where there was genetic modification of molecules that could regulate cell numbers in the bone. And so in particular we used a system that had been worked out by Hank Kronenberg, where he had a constitutively active parathyroid hormone receptor that was expressed under the control of an osteoblastic cell specific promoter. Colleagues were, at the same time, conducting a series of conditional deletions of the BMP receptor 1a, which ended up having a very similar phenotype. And that phenotype was basically to increase the number of osteolineage cells and with that, a concurrent increase in the number of hematopoietic stem and progenitors. That led to the hypothesis that these cells were central players in being able to regulate stem cells. But it was subsequent work that further defined that. And there was the genetic depletion of cells conducted by two laboratories-- one of which used a thymidine kinase being expressed under control of a bone specific promoter and treating the cells with a ganciclovir. The other was to use conditional deletion of osterix, which prevented the development of any osteoblastic cells. And in both those cases, there was a decrease in the number of osteoblastic cells and a decrease in the number of stem cells.