title: Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep.
abstract: Regeneration of complex tissues, such as kidney, liver, and cartilage, continues to be a scientific and translational challenge. Survival of ex vivo cultured, transplanted cells in tissue grafts is among one of the key barriers. Meniscus is a complex tissue consisting of collagen fibers and proteoglycans with gradient phenotypes of fibrocartilage and functions to provide congruence of the knee joint, without which the patient is likely to develop arthritis. Endogenous stem/progenitor cells regenerated the knee meniscus upon spatially released human connective tissue growth factor (CTGF) and transforming growth factor-β3 (TGFβ3) from a three-dimensional (3D)-printed biomaterial, enabling functional knee recovery. Sequentially applied CTGF and TGFβ3 were necessary and sufficient to propel mesenchymal stem/progenitor cells, as a heterogeneous population or as single-cell progenies, into fibrochondrocytes that concurrently synthesized procollagens I and IIα. When released from microchannels of 3D-printed, human meniscus scaffolds, CTGF and TGFβ3 induced endogenous stem/progenitor cells to differentiate and synthesize zone-specific type I and II collagens. We then replaced sheep meniscus with anatomically correct, 3D-printed scaffolds that incorporated spatially delivered CTGF and TGFβ3. Endogenous cells regenerated the meniscus with zone-specific matrix phenotypes: primarily type I collagen in the outer zone, and type II collagen in the inner zone, reminiscent of the native meniscus. Spatiotemporally delivered CTGF and TGFβ3 also restored inhomogeneous mechanical properties in the regenerated sheep meniscus. Survival and directed differentiation of endogenous cells in a tissue defect may have implications in the regeneration of complex (heterogeneous) tissues and organs.
authors.affiliation: Tissue Engineering and Regenerative Medicine Laboratory, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Special Surgery, 525 East 71st Street, New York, NY 10021, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rodeo
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Lisa Ann
authors.initials: LA
authors.lastname: Fortier
authors.affiliation: Tissue Engineering and Regenerative Medicine Laboratory, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Lu
authors.affiliation: Tissue Engineering and Regenerative Medicine Laboratory, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Cevat
authors.initials: C
authors.lastname: Erisken
authors.affiliation: Tissue Engineering and Regenerative Medicine Laboratory, Columbia University Medical Center, New York, NY 10032, USA. jmao@columbia.edu.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
mesh_terms: D000328:Adult; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D051445:Fibrocartilage / Q000737:chemistry; D006801:Humans; D008592:Menisci, Tibial / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology; D011108:Polymers / Q000737:chemistry*; D066330:Printing, Three-Dimensional; D011506:Proteins / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012038:Regeneration; D012756:Sheep; D054457:Tissue Scaffolds; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D001672:Biocompatible Materials; C526317:CCN2 protein, human; D011108:Polymers; D011506:Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor