Functional tissue regeneration remains an elusive goal for the treatment of a variety of traumatic injuries and chronic degenerative diseases that afflict a significant portion of the general population. Although mammals successfully regenerate tissues during early stages of fetal development, this trait is irreversibly lost as mammals mature. The contrast between embryonic and adult wound healing mechanisms suggests that the microenvironment that facilitates proper tissue regeneration in embryos is distinctly different from that of adult somatic tissues. Therefore, obtaining and introducing the molecular constituents of embryonic microenvironments to sites of adult tissue injury or disease may alter the course of endogenous tissue repair, yielding functional neo-tissues. A number of stem cell therapies are being developed in an attempt to restore the cellularity of damaged tissues, and in most instances, despite low levels of engraftment and differentiation into mature cell types, transplanted stem cells evoke significant functional improvements in the regenerative potential of tissues, indicating that the factors produced by stem cells may in fact directly impact tissue morphogenesis. This concept suggests a potential paradigm shift in the development and application of regenerative stem cell therapies - from cell replacement substitutes to biocatalytic agents of tissue regeneration. Thus, the objective of this proposal is to develop engineered biomaterials capable of sequestering morphogenic factors produced by differentiating embryonic stem cells (ESCs) and to deliver ESC-derived morphogens to adult wound sites in order to enhance tissue regeneration. These studies will provide new insights into the regenerative function of pluripotent stem cells and mechanisms of mammalian tissue repair, as well as directly lead to the development of a new class of regenerative molecular therapeutics to treat a variety of traumatic injuries and degenerative diseases.

Public Health Relevance

The inability of adult mammals to restore normal tissue structure and function following traumatic injury or due to degenerative disease remains a leading challenge to the development of effective biomedical therapies. Stem cells are capable of differentiating into cell types that could be used to replace cells lost due to injury and disease, but stem cells also contribute unique combinations of molecules capable of improving tissue repair. This proposal seeks to develop a clinically translatable and controlled approach to deliver potent molecular factors produced by stem cells via engineered biomaterials in order to promote the regeneration of injured tissues in adult mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR062006-06
Application #
8913670
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Tseng, Hung H
Project Start
2011-09-16
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
6
Fiscal Year
2015
Total Cost
$414,192
Indirect Cost
$164,192
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
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Miller, Tobias; Goude, Melissa C; McDevitt, Todd C et al. (2014) Molecular engineering of glycosaminoglycan chemistry for biomolecule delivery. Acta Biomater 10:1705-19
Hettiaratchi, Marian H; Miller, Tobias; Temenoff, Johnna S et al. (2014) Heparin microparticle effects on presentation and bioactivity of bone morphogenetic protein-2. Biomaterials 35:7228-38
Goude, Melissa C; McDevitt, Todd C; Temenoff, Johnna S (2014) Chondroitin sulfate microparticles modulate transforming growth factor-?1-induced chondrogenesis of human mesenchymal stem cell spheroids. Cells Tissues Organs 199:117-30

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