Our long-term goal is to engineer hematopoietic bone ex vivo to treat disorders of both bone and hematopoiesis. The specific goal of this application is to produce bone that contains marrow with pluripotent, repopulating stem cells that can fulfill the long-term regenerative needs of patients, as well as provide structural integrity for the repair of bone defects. To achieve this goal, we have assembled a team of interactive investigators from Baylor College of Medicine (BCM) and Rice that have the required expertise in biology and engineering, which includes: hematopoiesis and stem cell biology (Goodell, BCM), bone development (Davis, BCM), vascular development (Hirschi, BCM & Rice), biomaterials and bioreactors (West and Mikos, Rice) and bioimaging (Barry and Sevick, BCM and Rice). Our overarching hypotheses are that the steps that lead to bone formation and the establishment of functional marrow and vasculature are dissectible and definable in a model of de novo bone formation; furthermore, by understanding the sequence and kinetics of the cellular and molecular events needed for this process, we will gain insight into how to recapitulate hematopoietic bone formation ex vivo for the propagation of pluripotent HSC in vitro and in vivo. Toward addressing these hypotheses, we have established a model of de novo bone formation in which vascularized, marrow-filled bone was generated in vivo, and demonstrated that the marrow formed within this bone structure enables the survival and propagation of functional HSC that are capable of long-term reconstitution of all blood cell lineages in vivo. We have begun the dissect and define the molecular steps that lead to hematopoietic bone formation and have established bioimaging techniques needed to track the fate and function of marrow-derived cells ex vivo and in vivo. We have designed and generated biomaterials that will enable cellular survival and propagation, and bioreactors in which bone and blood vessels are readily fabricated. In this application, we will integrate all of these components to engineer hematopoietic bone and test its functions in vitro and in vivo. Furthermore, we have established necessary links to BCM and Rice technology transfer offices to facilitate the transition of our research into biotech and clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB005173-03
Application #
7276080
Study Section
Special Emphasis Panel (ZRG1-MOSS-G (52))
Program Officer
Hunziker, Rosemarie
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$1,107,420
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Goldberg, Joshua S; Vadakkan, Tegy J; Hirschi, Karen K et al. (2013) A computational approach to detect gap junction plaques and associate them with cells in fluorescent images. J Histochem Cytochem 61:283-93
Rossi, Lara; Lemoli, Roberto M; Goodell, Margaret A (2013) Gpr171, a putative P2Y-like receptor, negatively regulates myeloid differentiation in murine hematopoietic progenitors. Exp Hematol 41:102-12
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Poché, Ross A; Sharma, Ramaswamy; Garcia, Monica D et al. (2012) Transcription factor FoxO1 is essential for enamel biomineralization. PLoS One 7:e30357
Culver, James C; Hoffmann, Joseph C; Poché, Ross A et al. (2012) Three-dimensional biomimetic patterning in hydrogels to guide cellular organization. Adv Mater 24:2344-8

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