Broad Center for Stem Cell Research and Jonsson Comprehensive Cancer Center
TheChuteLab
Research
Role of the Vascular Niche in Regulating Hematopoietic Stem Cell Fate
Recent evidence suggests that both normal and cancerous stem cells depend upon their microenvironments or “niches” to receive signals which promote survival, proliferation and self-renewal. However, the mechanisms through which the microenvironment cells regulate hematopoietic stem cell (HSC) homeostasis and regeneration remain largely unknown. In our laboratory, we study novel intrinsic and extrinsic mechanisms which regulate hematopoietic stem cell self-renewal, differentiation and regeneration. We have particularly focused on characterizing the role of bone marrow endothelial cells (BM ECs) in regulating normal and malignant hematopoiesis and the soluble factors elaborated by ECs which regulate these processes (1-3). We discovered the function of the enzyme, ALDH1 (4), in regulating HSC differentiation and recently described the function of two vascular niche-derived paracrine factors, pleiotrophin and epidermal growth factor, in regulating HSC regeneration in vivo (5,6). Currently, we are utilizing cell-specific genetic models in mice to dissect the precise mechanisms through which BM microenvironment cells regulate the fate of malignant myeloid leukemia stem cells and multiple myeloma-initiating cells. Our broad objective is to leverage our discoveries of novel mechanistic targets within the stem cell niche to develop therapies to augment normal hematopoiesis and to inhibit cancer stem cell growth in patients.
1. Chute JP, Muramoto G, Fung J, Oxford C. Soluble factors elaborated by human brain endothelial cell induce the concomitant expansion of purified BM CD34+CD38- cells and SCID repopulating cells. Blood 105:576-583, 2005.
2. Chute JP, Muramoto G, Salter AB, Meadows S, Rickman D, Chen B, Himburg H, Chao N. Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice. Blood 109:2365-2372, 2007.
3. Salter A, Meadows S, Muramoto G, Himburg H, Doan P, Daher P, Russell L, Chen B, Chao N, Chute JP. Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo. Blood 113:2104-2107, 2009.
4. Chute JP, Muramoto G, Whitesides J, Colvin M, Safi R, Chao N, McDonnell D. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci, USA 103:11707-11712, 2006.
5. Himburg H, Muramoto G, Daher P, Meadows S, Russell J, Doan P, Chi J, Salter A, Lento W, Reya T, Chao N, Chute JP. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Medicine 16:475-482, 2010.
6. Doan PL, Himburg HA, Helms K, Russell JL, Fixsen E, Quarmyne M, Harris JR, Deoliviera D, Sullivan JM, Chao NJ, Kirsch DG, Chute JP. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nature Medicine 19:295-304, 2013.
Recent evidence suggests that both normal and cancerous stem cells depend upon their microenvironments or “niches” to receive signals which promote survival, proliferation and self-renewal. However, the mechanisms through which the microenvironment cells regulate hematopoietic stem cell (HSC) homeostasis and regeneration remain largely unknown. In our laboratory, we study novel intrinsic and extrinsic mechanisms which regulate hematopoietic stem cell self-renewal, differentiation and regeneration. We have particularly focused on characterizing the role of bone marrow endothelial cells (BM ECs) in regulating normal and malignant hematopoiesis and the soluble factors elaborated by ECs which regulate these processes (1-3). We discovered the function of the enzyme, ALDH1 (4), in regulating HSC differentiation and recently described the function of two vascular niche-derived paracrine factors, pleiotrophin and epidermal growth factor, in regulating HSC regeneration in vivo (5,6). Currently, we are utilizing cell-specific genetic models in mice to dissect the precise mechanisms through which BM microenvironment cells regulate the fate of malignant myeloid leukemia stem cells and multiple myeloma-initiating cells. Our broad objective is to leverage our discoveries of novel mechanistic targets within the stem cell niche to develop therapies to augment normal hematopoiesis and to inhibit cancer stem cell growth in patients.
1. Chute JP, Muramoto G, Fung J, Oxford C. Soluble factors elaborated by human brain endothelial cell induce the concomitant expansion of purified BM CD34+CD38- cells and SCID repopulating cells. Blood 105:576-583, 2005.
2. Chute JP, Muramoto G, Salter AB, Meadows S, Rickman D, Chen B, Himburg H, Chao N. Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice. Blood 109:2365-2372, 2007.
3. Salter A, Meadows S, Muramoto G, Himburg H, Doan P, Daher P, Russell L, Chen B, Chao N, Chute JP. Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo. Blood 113:2104-2107, 2009.
4. Chute JP, Muramoto G, Whitesides J, Colvin M, Safi R, Chao N, McDonnell D. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci, USA 103:11707-11712, 2006.
5. Himburg H, Muramoto G, Daher P, Meadows S, Russell J, Doan P, Chi J, Salter A, Lento W, Reya T, Chao N, Chute JP. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Medicine 16:475-482, 2010.
6. Doan PL, Himburg HA, Helms K, Russell JL, Fixsen E, Quarmyne M, Harris JR, Deoliviera D, Sullivan JM, Chao NJ, Kirsch DG, Chute JP. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nature Medicine 19:295-304, 2013.