This application is designed to develop new therapeutic approaches for cartilage restoration, which in turn will reduce morbidity and mortality from degenerative joint disease. None of the current cartilage repair strategies has generated long lasting hyaline cartilage replacement tissue that meets functional demands placed upon this tissue in vivo. I hypothesize that human pluripotent stem cell (PSC) derived chondroprogenitor cells (ChPC) or the precursors of ChPC may have greater potential for use in regenerative medicine than adult articular chondrocytes and adult mesenchymal stem cells based on their chondrogenic commitment, lineage potential and proliferative ability. Further I propose that studies to identify and characterize the stages of human chondrogenesis are needed to insure successful generation and isolation of identical ChPC from PSC. Thus, the overall goal of the proposed study is to define the stages through which ChPC are generated from multipotent mesodermal ancestors, with the ultimate objective of producing ChPC with the highest potential for use in regenerative medicine. Our group has recently reported the earliest embryonic mesodermal progenitor (EMP) produced during human PSC differentiation. EMPs are ancestors of more lineage restricted mesenchymal progenitor cells (osteo- and chondrogenic), hematoendothelial and cardiovascular progenitors. I will use this novel EMP population to recapitulate early stages of embryonic mesenchyme generation, chondrogenesis and eventually, articular cartilage formation. I also carried out pilot immunophenotypical characterization of primary ChPC at early stages of human embryogenesis. In combination with in vitro studies of primary and induced PSC (iPSC)-derived ChPC populations, a xenograft animal model and in vivo bioluminescence imaging will be utilized in the following specific aims to study the potential of iPSC-derived ChPC for use in regenerative medicine. This application is submitted by Dr. Denis Evseenko, an investigator in the field of developmental and stem cell biology whose objective is to transition into an independent researcher. As part of his career development he will receive training in the new fields of cartilage biology and xenograft models of osteoarthritis. In addition this proposal outlines the course work through the NIH funded K30 program at UCLA and other training activities that will help Denis to increase his knowledge base and improve his grant writing skills and ability to execute translational clinical research. This application is strongly supported by the Orthopedic Research Hospital at UCLA. Dr John Adams who is a Vice Chair of Research Department of Orthopedic Surgery and Director of Orthopedic Hospital Research Center at UCLA will act as a primary mentor for this application. In summary, this application will serve not only to address immediate and long term scientific questions in the field of chondrogenesis, but also the career development of Dr Evseenko into a successful independent researcher.

Public Health Relevance

Degenerative joint disease or osteoarthritis (OA) is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. According to the National Arthritis Data Workgroup, OA affected 26.9 million adults in 2005 in the United States, and the number is projected to increase up to 40% by 2030, therefore making joint surface restoration a priority. This application is highly relevant to the field of health science because it's designed to develop new therapeutic approaches for cartilage restoration, which in turn will reduce morbidity and mortality from degenerative joint disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Tyree, Bernadette
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Hicks, Michael R; Hiserodt, Julia; Paras, Katrina et al. (2018) ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. Nat Cell Biol 20:46-57
Shkhyan, Ruzanna; Van Handel, Ben; Bogdanov, Jacob et al. (2018) Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann Rheum Dis 77:760-769
Ferguson, Gabriel B; Van Handel, Ben; Bay, Maxwell et al. (2018) Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes. Nat Commun 9:3634
Wu, Ling; Zhang, Shu; Shkhyan, Ruzanna et al. (2017) Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration. JCI Insight 2:e88553
Chin, Chee Jia; Cooper, Aaron R; Lill, Georgia R et al. (2016) Genetic Tagging During Human Mesoderm Differentiation Reveals Tripotent Lateral Plate Mesodermal Progenitors. Stem Cells 34:1239-50
Richardson, Wade; Wilkinson, Dan; Wu, Ling et al. (2015) Ensemble multivariate analysis to improve identification of articular cartilage disease in noisy Raman spectra. J Biophotonics 8:555-66
Wu, L; Petrigliano, F A; Ba, K et al. (2015) Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis. Osteoarthritis Cartilage 23:308-18
Kim, Jinku; Lin, Brian; Kim, Soyon et al. (2015) TGF-?1 conjugated chitosan collagen hydrogels induce chondrogenic differentiation of human synovium-derived stem cells. J Biol Eng 9:1
Wu, Ling; Gonzalez, Stephanie; Shah, Saumya et al. (2014) Extracellular matrix domain formation as an indicator of chondrocyte dedifferentiation and hypertrophy. Tissue Eng Part C Methods 20:160-8
Vadivel, Kanagasabai; Ponnuraj, Sathya-Moorthy; Kumar, Yogesh et al. (2014) Platelets contain tissue factor pathway inhibitor-2 derived from megakaryocytes and inhibits fibrinolysis. J Biol Chem 289:31647-61

Showing the most recent 10 out of 16 publications