The main goal of this proposal (Project 6 of 11 of a U54 Consortium grant entitled, """"""""SysCODE: Systemsbased Consortium for Organ Design and Engineering"""""""") is to define engineering principles and microstructural design criteria that when combined with the molecular blueprint uncovered by this Consortium will permit us to fabricate biomimetic materials with appropriate mechanical and chemical signals necessary to induce organ regeneration. We will define how micromechanical forces generated by tissue cells and resisted by extracellular matrices (ECMs) with different mechanical compliance and internal microstructure contribute locally to the regional tissue shape transformations and progressive structural remodeling that mediate morphogenesis and hierarchical self assembly of complex organs. The long term goal is to use the physical design criteria identified in this effort to fabricate multifunctional biomimetic scaffolds that can reprogram stem cells to recapitulate organ formation. These scaffolds will mimic the micromechanical features of living ECMs that control cell fate switching locally, and will spatially orient chemical and adhesive signals that. trigger appropriate developmental cascades. To identify fundamental design principles, we will break down this hierarchical self assembly process into individual steps or critical """"""""morphogenetic modules"""""""" ,(e.g., mesenchyme condensation, epithelial budding and folding, cell fate switching, and epithelial-mesenchymal transitions) that underlie epithelial-mesenchymal interactions during development of the tooth, as well as pancreatic islets and heart valves. Relevant molecular regulators and high throughput ECM fabrication strategies will be accessed through collaboration with other members of this Consortium. The new information, ECM materials and design criteria discovered in this proposal will then be integrated with the other projects to develop prototype materials for tissue and organ engineering.
The specific aims i nclude: 1) To analyze how cell-generated contractile forces and ECM micromechanics vary spatially during morphogenetic shape transformations in the developing tooth, 2) To determine the effects of altering endogenous cell-generated tensional forces or applying external mechanical loads on tooth development, and 3) To determine the effects of varying the mechanics, structure and chemistry of artificial ECMs on morphogenesis and cell fate switching in tooth, pancreatic islet and heart valve.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Linked Research project Grant (RL1)
Project #
5RL1DE019023-02
Application #
7502023
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Lumelsky, Nadya L
Project Start
2007-09-28
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$580,985
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Hashmi, Basma; Mammoto, Tadanori; Weaver, James et al. (2017) Mechanical induction of dentin-like differentiation by adult mouse bone marrow stromal cells using compressive scaffolds. Stem Cell Res 24:55-60
Mammoto, Tadanori; Mammoto, Akiko; Jiang, Amanda et al. (2015) Mesenchymal condensation-dependent accumulation of collagen VI stabilizes organ-specific cell fates during embryonic tooth formation. Dev Dyn 244:713-23
Memic, Adnan; Khademhosseini, Ali (2014) Finding the winning combination. Combinatorial screening of three dimensional niches to guide stem cell osteogenesis. Organogenesis 10:299-302
Campas, Otger; Mammoto, Tadanori; Hasso, Sean et al. (2014) Quantifying cell-generated mechanical forces within living embryonic tissues. Nat Methods 11:183-9
Hashmi, Basma; Zarzar, Lauren D; Mammoto, Tadanori et al. (2014) Developmentally-inspired shrink-wrap polymers for mechanical induction of tissue differentiation. Adv Mater 26:3253-7
Arany, Praveen R; Cho, Andrew; Hunt, Tristan D et al. (2014) Photoactivation of endogenous latent transforming growth factor-?1 directs dental stem cell differentiation for regeneration. Sci Transl Med 6:238ra69
Brock, Amy; Krause, Silva; Li, Hu et al. (2014) Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. Sci Transl Med 6:217ra2
Dolatshahi-Pirouz, Alireza; Nikkhah, Mehdi; Gaharwar, Akhilesh K et al. (2014) A combinatorial cell-laden gel microarray for inducing osteogenic differentiation of human mesenchymal stem cells. Sci Rep 4:3896
Mammoto, Tadanori; Mammoto, Akiko; Ingber, Donald E (2013) Mechanobiology and developmental control. Annu Rev Cell Dev Biol 29:27-61
Mammoto, Tadanori; Chen, Jing; Jiang, Elisabeth et al. (2012) LRP5 regulates development of lung microvessels and alveoli through the angiopoietin-Tie2 pathway. PLoS One 7:e41596

Showing the most recent 10 out of 14 publications