Areas of Interest
NK Cell Development and Function
NK cells are important cells of the immune system with active participation on the control of newly formed and metastatic tumors, early elimination of virally infected cells, and
rejection of transplants especially bone marrow. They also play important roles on immunoregulation, modulating later immune responses by conventional lymphocytes. We are aiming to
understand the role of common gamma chain cytokines, mostly IL-7 and IL-15, on defining the generation of NK cells from early lymphoid progenitors in the bone marrow and on maintaining
the homeostatic levels of the NK cell compartment in periphery after activation. A major emphasis has been placed on studying the role of survival mediated by members of the bcl-2 family
of antiapoptotic molecules. We utilize as a model of NK cell activation, infection of different genetically modifies mice with murine cytomegalovirus, an infectious agent that is
controlled almost exclusively by NK cells in the early stages of infection.
Hematopoietic Stem Cell Niches and Bone Remodeling
Hematopoiesis and bone formation, are tightly co regulated biological processes during development as well as during bone remodeling. One of the critical cells involved in bone biology,
the osteoclast, is of hematopoietic origin. In addition, the establishment of hematopoiesis in the bone marrow is dependent on the correct development of osteoblasts, the main cells
responsible to form bone.
In collaboration with Drs. Joseph Lorenzo and Kyeong Lee, we are characterizing the development of osteoclasts from myeloid progenitors in the bone marrow, their relationship with the
generation of other myeloid cells like macrophages and dendritic cells, and the potential to reconstitute osteoclast populations in vivo through bone marrow progenitor transplantation.
We are also interested in studying the regulation of these progenitors during physiological and pathological conditions with the goal to translate our findings to a better understanding
of osteoporosis, and hopefully to identify targets for therapeutic intervention.
In collaboration with Drs. David Rowe, Alex Lichtler, and Steve Clark, we are studying the regulation of hematopoiesis by osteoblastogenesis. We recently found that blocking
osteoblast development at defined stages alters dramatically the hematopoietic process in the bone marrow. This finding has allowed us to consider osteoblast arrest as a precondition
protocol to achieve hematopoietic reconstitution via hematopoietic stem cell transplantation. We are using these systems to understand the regulation of hematopoietic niches by
osteoblasts during development and during transplantation. In addition, we are studying the development of osteoblasts from early progenitors using flow cytometry techniques. We hope in
this way to identify new markers for different stages of osteoblast development and hopefully design reproducible protocols for the isolation of mesenchymal progenitors. These will be
valuable not only for the study of the biology of osteoblast development, but also to obtain cells for regenerative therapies.
Design of Techniques and Reagents to Characterize and Isolate Cells at Early Stages of Human Development
The design of methods for the correct identification of stem cells is crucial if we would like to use them in regenerative therapies. The generation of antibodies against cell surface
molecules provides one of the best approaches not only to characterize different cell types but also to isolate them. This approach has been used successfully to isolate hematopoietic
stem cells, the stem cells that form all the blood cellular components. However, the development of antibodies with the ability to correctly identify and isolate other types of human
stem cells have been limited as they are present in very low abundance and they localize tightly associated to tissues, making it very difficult to obtain enough numbers of them.
Our group has developed unique tracking systems for musculoskeletal development to visualize progenitors with the ability to develop into cartilage, bone, fat and muscle. These
systems are based on genetic techniques that add genetic information to human embryonic stem cells to make them express a fluorescent protein at defined stages of their development. This
fluorescence can be visualized by exciting the cells with ultraviolet light allowing the identification and isolation of cells at such specific developmental stages.
Genetically modified human ES cells, containing such trackers of musculoskeletal development, will be differentiated toward specific stem cells able to produce cartilage, bone, fat
and muscle. At different stages during their progression, these cells will be fractionated and used to immunize experimental animals for generation of specific antibodies. These
antibodies will be characterized, purified, and tested for their ability to identify cells with the potential to generate one or more of the target cell types.
We predict that we will generate reagents allowing us identify discrete stages of musculoskeletal development. These will be extremely useful tools for the understanding and the
diagnosis of developmental and genetic diseases affecting these tissues. In addition, using these antibodies together with powerful cell fractionation techniques, we expect to design
standard methods for the isolation of specific stem cells, derived from hES cells or from adult tissues, to be used in cell replacement therapies for damaged cartilage, bone and muscle.
Publications
Selected Publications
Boban, I., Jacquin, C., Prior, K., Barisic-Dujmovic, T., Maye, P., Clark, S., and H.L. Aguila. “The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of
genes in both osteoblast and osteoclast lineage cells” Bone 39:1302-1312. 2006.
Maxwell, J.R., Yadav, R., Rossi, R.J., Ruby, C.E., Weinberg, A.D., Aguila, H.L., and A.T. Vella. “IL-18 bridges innate and adaptive immunity through IFN and the CD134 pathway” J.
Immunology 177:234-245. 2006.
Aguila, H.L. “Regulation of hematopoietic niches by sympathetic innervation”. BioEssays 28:687-691. 2006.
Jacquin, C, Gran, D.E., Lee, S.K., Lorenzo, J.A., and H.L. Aguila. “Identification of multiple osteoclast precursor populations in murine bone marrow” J. Bone and Miner Res. 21:67-77.
2006.
Aguila, H.L., and D.W. Rowe. “Skeletal development, bone remodeling, and hematopoiesis”. Immunol. Rev. 208:7-18. 2005.
Schluns K.S., Nowak E.C., Cabrera-Hernandez A., Puddington L., Lefrançois L., Aguila H.L. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor
alpha expression. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5616-21. Epub 2004 Apr 01.
Visnjic D., Kalajzic Z., Rowe D.W., Katavic V., Lorenzo J., Aguila H.L. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004 May
1;103(9):3258-64.
Katavic V., Grcevic D., Lee S.K., Kalinowski J., Jastrzebski S., Dougall W., Anderson D., Puddington L., Aguila H.L., Lorenzo J.A. The surface antigen CD45R identifies a population of
estrogen-regulated murine marrow cells that contain osteoclast precursors. Bone. 2003 Jun;32(6):581-90.
Cooper M.A., Bush J.E., Fehniger T.A., VanDeusen J.B., Waite R.E., Liu Y., Aguila H.L., Caligiuri M.A. In vivo evidence for a dependence on interleukin 15 for survival of natural
killer cells. Blood. 2002 Nov 15;100(10):3633-8.
Visnjic D., Kalajzic I., Gronowicz G., Aguila H.L., Clark S.H., Lichtler A.C., Rowe D.W. Conditional ablation of the osteoblast lineage in Col2.3deltatk transgenic mice. J Bone Miner
Res. 2001 Dec;16(12):2222-31.
Kim S., Iizuka K., Aguila H.L., Weissman I.L., Yokoyama W.M. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci U S A. 2000 Mar
14;97(6):2731-6.
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