Back pain, a significant source of morbidity in our society, is directly related to the pathology of the intervertebral disc. At present, the treatment of degenerative disc disease consists of therapies, both conservative and invasive, that are aimed at symptomatic relief. Recent advances in the understanding of tissue repair and stem cell biology have served to identify possible new approaches to rebuild diseased/degenerate tissues. Accordingly, the goal of the investigations described in this proposal is to develop a """"""""tissue engineering"""""""" based approach to disc therapy.
The Specific Aims of the investigation are: 1. To examine the differentiation of MSC into a nucleus pulposus-like cell; to evaluate the commitment and fate of these engineered cells in an in vitro cell and organ culture system. MSC will be maintained under conditions that enhance differentiation into a nucleus pulposus phenotype. At selected time intervals, differentiation of the disc cells towards a phenotype consistent with that of the nucleus pulposus will be assessed. We will test the hypothesis that the unique micro-environment of the intervertebral disc serves to enhance the differentiation of MSC to cells displaying a nucleus pulposus-like phenotype. 2. To isolate a notochordal population of cells from the nucleus pulposus; to examine the impact of these cells on the commitment of MSC to the nucleus pulposus phenotype. We will examine the impact of notochordal cells, isolated from the nucleus pulposus of the young rat, on the differentiation of MSC and the formation of a nucleus pulposus-like tissue. We will co-culture notochordal with the pre-differentiated MSC prior to their insertion into the nucleus pulposus cavity. We will test the hypothesis that cells of notochordal origin stimulate the expression of the nucleus pulposus phenotype. 3. To assess whether transplanted MSC can be used in vivo to repopulate the rat nucleus pulposus. Suspended in an injectable hydrogel, we will surgically transplant pre-differentiated MSC into the nucleus pulposus cavity of normal rat discs in vivo. We will evaluate the vitality of the cells and their creation of a nucleus pulposus-like tissue. Outcomes from this study will validate the in vitro studies performed in Specific Aims 1 and 2 and permit us to test the hypothesis that MSC could differentiate into nucleus pulposus-like cells in vivo. In the long term, if successful, this approach to therapy will entail using patients' own cells for disc regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050087-03
Application #
7193532
Study Section
Special Emphasis Panel (ZRG1-MOSS-G (01))
Program Officer
Wang, Fei
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$322,128
Indirect Cost
Name
Thomas Jefferson University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Binch, Abbie L A; Shapiro, Irving M; Risbud, Makarand V (2016) Syndecan-4 in intervertebral disc and cartilage: Saint or synner? Matrix Biol 52-54:355-362
Schoepflin, Zachary R; Shapiro, Irving M; Risbud, Makarand V (2016) Class I and IIa HDACs Mediate HIF-1? Stability Through PHD2-Dependent Mechanism, While HDAC6, a Class IIb Member, Promotes HIF-1? Transcriptional Activity in Nucleus Pulposus Cells of the Intervertebral Disc. J Bone Miner Res 31:1287-99
Suyama, Kaori; Silagi, Elizabeth S; Choi, Hyowon et al. (2016) Circadian factors BMAL1 and ROR? control HIF-1? transcriptional activity in nucleus pulposus cells: implications in maintenance of intervertebral disc health. Oncotarget 7:23056-71
Tian, Ye; Yuan, Wen; Li, Jun et al. (2016) TGF? regulates Galectin-3 expression through canonical Smad3 signaling pathway in nucleus pulposus cells: implications in intervertebral disc degeneration. Matrix Biol 50:39-52
Li, Jun; Yuan, Wen; Jiang, Shuai et al. (2015) Prolyl-4-hydroxylase domain protein 2 controls NF-?B/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus. J Biol Chem 290:7195-207
Ye, Wei; Zhou, Jie; Markova, Dessislava Z et al. (2015) Xylosyltransferase-1 expression is refractory to inhibition by the inflammatory cytokines tumor necrosis factor ? and IL-1? in nucleus pulposus cells: novel regulation by AP-1, Sp1, and Sp3. Am J Pathol 185:485-95
Choi, Hyowon; Johnson, Zariel I; Risbud, Makarand V (2015) Understanding nucleus pulposus cell phenotype: a prerequisite for stem cell based therapies to treat intervertebral disc degeneration. Curr Stem Cell Res Ther 10:307-16
Shapiro, Irving M; Landis, William J; Risbud, Makarand V (2015) Matrix vesicles: Are they anchored exosomes? Bone 79:29-36
Johnson, Zariel I; Gogate, Shilpa S; Day, Rebecca et al. (2015) Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: Novel HIF-1-mediated regulation of aquaporins in NP cells. Oncotarget 6:11945-58
Gorth, Deborah J; Shapiro, Irving M; Risbud, Makarand V (2015) Discovery of the drivers of inflammation induced chronic low back pain: from bacteria to diabetes. Discov Med 20:177-84

Showing the most recent 10 out of 64 publications