title: Human Cartilage-Derived Progenitor Cells From Committed Chondrocytes for Efficient Cartilage Repair and Regeneration.
abstract: Articular cartilage is not a physiologically self-renewing tissue. Injury of cartilage often progresses from the articular surface to the subchondral bone, leading to pathogenesis of tissue degenerative diseases, such as osteoarthritis. Therapies to treat cartilage defects using autologous chondrocyte-based tissue engineering have been developed and used for more than 20 years; however, the challenge of chondrocyte expansion in vitro remains. A promising cell source, cartilage stem/progenitor cells (CSPCs), has attracted recent attention. Because their origin and identity are still unclear, the application potential of CSPCs is under active investigation. Here we have captured the emergence of a group of stem/progenitor cells derived from adult human chondrocytes, highlighted by dynamic changes in expression of the mature chondrocyte marker, COL2, and mesenchymal stromal/stem cell (MSC) marker, CD146. These cells are termed chondrocyte-derived progenitor cells (CDPCs). The stem cell-like potency and differentiation status of CDPCs were determined by physical and biochemical cues during culture. A low-density, low-glucose 2-dimensional culture condition (2DLL) was critical for the emergence and proliferation enhancement of CDPCs. CDPCs showed similar phenotype as bone marrow mesenchymal stromal/stem cells but exhibited greater chondrogenic potential. Moreover, the 2DLL-cultured CDPCs proved efficient in cartilage formation both in vitro and in vivo and in repairing large knee cartilage defects (6-13 cm(2)) in 15 patients. These findings suggest a phenotype conversion between chondrocytes and CDPCs and provide conditions that promote the conversion. These insights expand our understanding of cartilage biology and may enhance the success of chondrocyte-based therapies.
  
  
  CONCLUSIONS
  Injury of cartilage, a non-self-repairing tissue, often progresses to pathogenesis of degenerative joint diseases, such as osteoarthritis. Although tissue-derived stem cells have been shown to contribute to tissue renewal and homeostasis, the derivation, biological function, and application potential of stem/progenitor cells found in adult human articular cartilage are incompletely understood. This study reports the derivation of a population of cartilage stem/progenitor cells from fully differentiated chondrocytes under specific culture conditions, which have the potential to reassume their chondrocytic phenotype for efficient cartilage regeneration. These findings support the possibility of using in vitro amplified chondrocyte-derived progenitor cells for joint cartilage repair.
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Center for Cellular Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Yangzi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Orthopaedics, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Chinese Orthopaedic Regenerative Medicine Group, Hangzhou, People's Republic of China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Changchang
authors.initials: C
authors.lastname: Hu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Tong
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Chinese Orthopaedic Regenerative Medicine Group, Hangzhou, People's Republic of China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Dante
authors.initials: D
authors.lastname: Neculai
authors.affiliation: Center for Cellular Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA hwoy@zju.edu.cn rst13@pitt.edu.
authors.forename: Rocky S
authors.initials: RS
authors.lastname: Tuan
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Department of Orthopaedics, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China Chinese Orthopaedic Regenerative Medicine Group, Hangzhou, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China hwoy@zju.edu.cn rst13@pitt.edu.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Ouyang
mesh_terms: D002356:Cartilage / Q000254:growth & development* / Q000293:injuries; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010003:Osteoarthritis / Q000473:pathology / Q000628:therapy*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology*; D023822:Tissue Engineering
keywords: Cartilage repair; Cell transplantation; Chondrocytes; Dedifferentiation; Osteoarthritis; Stem and progenitor cells; Stem cell markers; Stemness; Tissue regeneration