| |
David T. Scadden, M.D.
Professor of Medicine, Harvard Medical School
scadden.david@mgh.harvard.edu
Using Stem Cell Biology to Enhance Bone Marrow Transplantation
The focus of our laboratory is stem cells. Our goals are to understand how stem cells are regulated, develop rational methods for manipulating them, and apply stem cell therapies to regenerate immunity in cancer and AIDS.
There are three basic hurdles to using stem cells more effectively in medical care. The first is cell growth. These cells divide rarely and are deeply quiescent in the body, properties we have shown are essential for longevity but are problematic for generating cell-based therapies. We have identified molecular brakes that restrict the proliferation of these cells. We have also shown that by manipulating these molecules, the brake on cell division can be released and human stem cells expanded. Our results indicate that this can be accomplished outside the body without sacrificing the wide range of mature cell types these cells can become. By focusing on controls that dictate whether or not an adult stem cell divides and whether a dividing stem cell will create more stem cells, we have assembled a number of molecular tools to induce stem cell expansion. Linking these basic studies to practical methods for increasing stem cell numbers to use in patient care is our highest priority.
How cells know when to divide in the body is an extension of this priority. We sought to define how the body manages stem cells so that we might strategically use similar approaches therapeutically. Reasoning that blood cell development occurs in bone because bone is providing some key regulatory information, we have examined genetically altered mice with distinct changes in their bones. One of these has allowed us to define that the bone-forming cell, the osteoblast, is a key participant in controlling stem cell numbers. By activating this cell with a hormone now used in clinical practice for osteoporosis, we have shown a marked impact on stem cells. This resulted in dramatic improvements in survival after bone marrow transplantation in animal models. These studies are the basis for now testing this approach in humans who need a transplant to treat lymphoma.
The second barrier to broader stem cell use is the inefficient manner in which they are delivered to sites of need. Within the body, cell movement is often guided by molecular cues including signals elaborated from neighboring tissues. The cues that guide stem cells are poorly understood and we have focused on identifying these, using the simple model of what the bone provides to lead blood stem cells into the bone marrow. By linking with outstanding bone physiologists and molecular imaging experts at MGH, we have identified signals that participate in moving and regulating stem cells in the body. These provide a basis for enhancing the delivery of stem cells to particular sites, specifically the bone marrow, where immune restoration begins.
Third in the list of hurdles is our limited understanding of what guides cells to undertake a specific path of maturation. With the broad range of options available to a stem cell, what determines whether it will become a T cell of the immune system or a red cell to deliver oxygen? We have begun to address this question by generating bioengineered constructs in which stem cells can mature into T cells and identifying molecules that influence the relative production of T cells from stem cells.
Combining the efforts to expand stem cells, target them to sites of action, and guide them to become the cells of greatest need is our long-term objective. Through the dedicated team effort of basic biologists and clinically oriented investigators, we envision a program where fundamental rules of stem cell biology are exploited to generate novel cell-based therapies for immune regeneration.
Selected Publications
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Bringhurst FR, Divieti P, Milner LA, Kronenberg H, Scadden DT. Osteoblastic cells regulate the hematopoetic stem cell niche. Nature 2003; 425:841-6.
Lee BC, Cheng T, Adams GB, Miura N, Lee SB, Attar EC, Saito Y, Olszak I, Dombkowski D, Olson DP, Hancock J, Haber DA, Luster AD, Scadden DT. P2Ylike receptor, GPR105, identifies and mediates chemotaxis of bone marrow restricted primitive hematopoietic cells. Genes Dev 2003; 17:1592-1604.
Stier S, Cheng T, Forkert R, Lutz C, Dombkowski DM, Lin J, Scadden DT. Ex vivo targeting of p21 Cip1/Waf1 permits relative expansion of human hematopoietic stem cells. Blood 2003; 1024:1260-6.
Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21 cip/waf1 . Science 2000; 287:1804-1808.
Cheng T, Rodrigues N, Dombkowski D, Stier S, Scadden DT. Stem cell repopulation efficiency, but not pool size, is governed by p27 kip1. Nat Med 2000; 6:1235-40.
Additional Publications
top
|
