Integrin specificity as a novel strategy for enhancing transplanted stem cell survival and tissue repair in vivo

Clark, Amy Yee lae

Title:

Integrin specificity as a novel strategy for enhancing transplanted stem cell survival and tissue repair in vivo

dc.contributor.advisor	García, Andrés J.
dc.contributor.author	Clark, Amy Yee lae
dc.contributor.committeeMember	Guldberg, Robert
dc.contributor.committeeMember	McDevitt, Todd
dc.contributor.committeeMember	Barker, Thomas
dc.contributor.committeeMember	Botchwey, Edward
dc.contributor.department	Mechanical Engineering
dc.date.accessioned	2017-06-07T17:37:55Z
dc.date.available	2017-06-07T17:37:55Z
dc.date.created	2016-05
dc.date.issued	2016-04-01
dc.date.submitted	May 2016
dc.date.updated	2017-06-07T17:37:55Z
dc.description.abstract	Despite the promising clinical results for the use of human mesenchymal stem cells (hMSC) in musculoskeletal defect treatment, inadequate control of cell survival, engraftment and fate limits the success of this cell-based therapy. Integrin-mediated cell adhesion plays a central role in tissue formation, maintenance, and repair by providing anchorage forces and triggering signals that regulate cell function. We hypothesize that biomaterials presenting integrin-specific adhesive motifs will direct hMSC engraftment and function to improve bone repair. The objective of this project is to engineer bioartificial hydrogels presenting integrin-specific ligands as biomimetic cell delivery vehicles for enhanced in vivo engraftment and function – an innovative strategy as it focuses on engineering specificity to integrin receptors to promote survival and cell-based repair without the use of exogenous growth factors. We investigated the performance of a cell-mediated degradable hydrogel functionalized with integrin-specific ligands in supporting the survival of transplanted hMSC and tissue repair in a segmental bone defect. This was accomplished by incorporating the adhesive 𝛂2𝛃1 integrin-specific GFOGER ligand, adhesive 𝛂v𝛃3 integrin-specific RGD ligand, non-adhesive RDG peptide, or non-adhesive GAOGER peptide combined with human mesenchymal stem cells in a protease-degradable PEG-maleimide hydrogel. Cell survival was tracked through transgenic luciferase expression and bone repair was monitored by microcomputer tomography. We hypothesized that hydrogel delivery vehicles that promoted cell viability in combination with the pro-osteogenic properties of the carrier would result in superior bone repair. We found that α2β1-specific GFOGER-functionalized hydrogels promoted enhanced hMSC survival and bone repair, with differential expression of vascularization and inflammation-related genes in vivo compared to RGD- or RDG-functionalized hydrogels, highlighting integrin-specificity as an important consideration in the design of cell delivery vehicles for engraftment and tissue repair. We have generated new insights into transplanted hMSC survival, engraftment and function in a bone repair model allowing for direct correlations among hydrogel formulation and integrin specificity, transplanted cell survival, and bone repair outcomes. This work is significant and innovative because improved design of cell delivery vehicles may improve efficacy of current hMSC therapies in the clinic.
dc.description.degree	Ph.D.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/58178
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	Integrin
dc.subject	Hydrogel
dc.subject	Mesenchymal stem cells
dc.subject	Bone repair
dc.subject	Immunomodulation
dc.title	Integrin specificity as a novel strategy for enhancing transplanted stem cell survival and tissue repair in vivo
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.advisor	García, Andrés J.
local.contributor.corporatename	George W. Woodruff School of Mechanical Engineering
local.contributor.corporatename	College of Engineering
relation.isAdvisorOfPublication	6236e450-228b-4532-8b5e-812316ac90f3
relation.isOrgUnitOfPublication	c01ff908-c25f-439b-bf10-a074ed886bb7
relation.isOrgUnitOfPublication	7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level	Doctoral