Gerald Spangrude
Professor of Pathology and of Medicine
B.S. University of Montana, Missoula
Ph.D. University of Utah
Research
My laboratory works with various models of stem cell biology. Two areas of research are of particular interest to us. In the first area, the laboratory utilizes NIH-approved human embryonic stem (hES) cell lines to investigate the development of blood during embryogenesis. These experiments allow us to study a human developmental question in a model system that is reproducible, since the cell lines can be maintained in culture indefinitely and can be induced to differentiate into blood lineages by manipulation of culture conditions. In contrast, analysis of blood development from adult-derived blood stem cells involves isolation of these cells from patient samples, which vary widely due to genetic differences, diagnosis, and the degree of prior treatment for disease. We are able to induce hES cells to differentiate into many of the normal blood lineage cells, opening up the possibility for us to study the molecular determinants underlying the process of blood development. We plan to apply gene transfer technology in this model system in order to develop in vitro models of human diseases such as hemoglobinopathies and leukemia.
Our second area of research interest pertaining to stem cell biology focuses on adult stem cell populations obtained from mouse bone marrow tissue. We have devoted many years to elucidating the developmental pathway leading from stem cell to mature lymphocyte in the mouse model. We have identified several intermediate stages in this process, and have adopted in vitro techniques that allow us to follow lymphoid development in a controlled culture environment. These studies will help us understand how lymphocyte cells are generated from adult stem cells, and will be useful in designing protocols to enhance lymphoid engraftment following bone marrow transplantation.
Using fluorescent antibodies as probes to label specific cell populations, we are able to identify and isolate the stem cells found in normal mouse and human bone marrow using fluorescence-activated cell sorting (FACS). This technology allows us to isolate defined cell populations that can then be studied in culture or in transplantation models. We can evaluate the functions of stem cell populations isolated after various treatments, such as chemotherapy, infections, inflammation, and during the aging process. We can also study how the cells respond to culture conditions and growth factors in order to better model the early stages of blood development in culture. This work will lead to a better understanding of the molecular control of blood development and eventual applications in clinical medicine.
References
1. Anderson DA, Wu Y, Jiang S, Zhang X, Streeter PR, Spangrude GJ, Archer DR, Fleming WH (2005) Donor marker infidelity in transgenic hematopoietic stem cells. Stem Cells 23:638
2. Perry SS, Wang H, Pierce LJ, Yang AM, Tsai S, Spangrude GJ (2004) L-selectin defines a bone marrow analog to the thymic early T-lineage progenitor. Blood 103:2990
3. Wang H, Spangrude GJ (2003) Aspects of early lymphoid commitment. Curr Opin Hematol 10:203
4. Spangrude GJ (2003) Future challenges for hematopoietic stem cell research. Biotechniques 35:1273
5. Spangrude GJ (2003) When is a stem cell really a stem cell? Bone Marrow Transplant 32 Suppl 1:S7
6. Perry SS, Pierce LJ, Slayton WB, Spangrude GJ (2003) Characterization of thymic progenitors in adult mouse bone marrow. J Immunol 170:1877
7. Kim M, Moon HB, Spangrude GJ (2003) Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 996:195
8. Wiesmann A, Searles AE, Pierce LJ, Spangrude GJ (2002) Effects of caspase inhibitors on hematopoietic engraftment after short-term culture. Cell Transplant 11:351
9. White C, Chen Z, Raetz E, Pulsipher M, Spangrude GJ, Slayton WB (2002) Using fluorescence-activated cell sorting followed by fluorescence in situ hybridization to study lineage relationships: the 8;21 translocation is present in neutrophils but not monocytes in a patient with severe congenital neutropenia and a granulocyte colony-stimulating factor-responsive clonal abnormality. Acta Paediatr Suppl 91:120
10. Spangrude GJ (2002) Divergent models of lymphoid lineage specification: do clonal assays provide all the answers? Immunol Rev 187:40
11. Slayton WB, Spangrude GJ, Chen Z, Greene WF, Virshup D (2002) Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome. J Pediatr Hematol Oncol 24:224
12. Slayton WB, Georgelas A, Pierce LJ, Elenitoba-Johnson KS, Perry SS, Marx M, Spangrude GJ (2002) The spleen is a major site of megakaryopoiesis following transplantation of murine hematopoietic stem cells. Blood 100:3975
13. Goldsby RE, Hays LE, Chen X, Olmsted EA, Slayton WB, Spangrude GJ, Preston BD (2002) High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc Natl Acad Sci U S A 99:15560
14. Cai J, Wu Y, Mirua T, Pierce JL, Lucero MT, Albertine KH, Spangrude GJ, Rao MS (2002) Properties of a fetal multipotent neural stem cell (NEP cell). Dev Biol 251:221
15. Mojica MP, Perry SS, Searles AE, Elenitoba-Johnson KS, Pierce LJ, Wiesmann A, Slayton WB, Spangrude GJ (2001) Phenotypic distinction and functional characterization of pro-B cells in adult mouse bone marrow. J Immunol 166:3042
16. Wiesmann A, Phillips RL, Mojica M, Pierce LJ, Searles AE, Spangrude GJ, Lemischka I (2000) Expression of CD27 on murine hematopoietic stem and progenitor cells. Immunity 12:193
17. Wiesmann A, Kim MJ, Georgelas A, Searles AE, Cooper DD, Green WF, Spangrude GJ (2000) Modulation of hematopoietic stem/progenitor cell engraftment by transforming growth factor- b . Exp Hematol 28:128
