Articular cartilage repair remains a challenge because of the lack of blood supply and accompanying posttraumatic inflammation. Despite the fact that autologous chondrocyte transplantation (ACT) is an option, cell source limitations retard the broad application of this approach clinically. Recently, there is increasing evidence indicating that adult stem cells are promising cell sources, particularly for stem cells derived from synovium (SDSCs), owing to its higher chondrogenic potential and lower hypertrophy. A small biopsy through arthroscopy can only provide a limited number of SDSCs for tissue regeneration, thus in vitro cell expansion is necessary; unfortunately, conventional expansion on plastic flasks causes cell senescence and loss of proliferation and differentiation capacity. Our recent reports indicated that decellularized extracellular matrix (dECM) deposited by SDSCs could enhance expanded stem cells' proliferation and chondrogenic potential. In this proposal, our central hypothesis is that dECM deposited by SDSCs can provide a superior tissue-specific matrix microenvironment for the optimal rejuvenation of human adult SDSCs in cartilage regeneration and defect repair. To achieve this hypothesis, we want to determine whether dECM deposited by SDSCs provides a superior matrix microenvironment for human adult SDSC rejuvenation compared to matrices from adipose- derived stem cells (ADSCs), urine-derived stem cells (UDSCs), or dermal fibroblasts (DFs) (Aim 1). We also plan to explore potential rejuvenation mechanisms by identifying specific matrix component(s) responsible for the rejuvenation of chondrogenic capacity via triggering the activation of critical integrin receptor(s) in expanded SDSCs (Aim 2). Lastly, a translational animal model will be used to evaluate SDSC/dECM repair strategies (Aim 3). Our objective is to determine the efficacy of this novel cell expansion system in providing a high quantity of high-quality SDSCs for the treatment of cartilage defects. This objective is consistent with our long-term goal which is to identify strategies for improved repair of cartilage defects in osteoarthritic patients using autologous stem cells. The primary impact of our expected findings would be significant not only in advancing the development of new generations of stem cell-based approaches for cartilage engineering and regeneration, but also in providing fundamental new knowledge regarding the interaction between stem cell and matrix microenvironment as well as potential mechanisms underlying stem cell rejuvenation by the surrounding stem cell matrix. Our dECM approach may also provide an excellent model for developing other tissue regeneration approaches.

Public Health Relevance

Autologous cell shortage and senescence are big hurdles in the clinical treatment of cartilage defects. Decellularized matrix deposited by tissue-specific stem cells provides a novel system for high-quality cell expansion. The aim of this study is to evaluate the feasibility of using tissue-specific matrix deposited by human synovial stem cells to expand human adult synovial stem cells from patients with cartilage defects for cartilage regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR067747-01A1
Application #
9028585
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$330,000
Indirect Cost
$110,000
Name
West Virginia University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Li, Mao; Yan, Jinku; Chen, Xi et al. (2018) Spontaneous up-regulation of SIRT1 during osteogenesis contributes to stem cells' resistance to oxidative stress. J Cell Biochem 119:4928-4944
Wang, Yifan; Chen, Guangdong; Yan, Jinku et al. (2018) Upregulation of SIRT1 by Kartogenin Enhances Antioxidant Functions and Promotes Osteogenesis in Human Mesenchymal Stem Cells. Oxid Med Cell Longev 2018:1368142
Li, Mao; Chen, Xi; Yan, Jinku et al. (2018) Inhibition of osteoclastogenesis by stem cell-derived extracellular matrix through modulation of intracellular reactive oxygen species. Acta Biomater 71:118-131
Sun, Yu; Chen, Song; Pei, Ming (2018) Comparative advantages of infrapatellar fat pad: an emerging stem cell source for regenerative medicine. Rheumatology (Oxford) 57:2072-2086
Chen, Xi; Yan, Jinku; He, Fan et al. (2018) Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway. Free Radic Biol Med 126:187-201
Chen, Song; Fu, Peiliang; Wu, Haishan et al. (2017) Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy, development and function. Cell Tissue Res 370:53-70
Pei, Ming (2017) Environmental preconditioning rejuvenates adult stem cells' proliferation and chondrogenic potential. Biomaterials 117:10-23
Chen, Xi; Li, Mao; Yan, Jinku et al. (2017) Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells. Alcohol Alcohol 52:289-297