title: Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons.
abstract: Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first-in-man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage-derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment-related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second-look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline-like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient-own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell-induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. Stem Cells 2017;35:256-264.
authors: Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Tommy S
authors: TS
authors: de Windt
authors: Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Lucienne A
authors: LA
authors: Vonk
authors: Cell Therapy Facility, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Ineke C M
authors: IC
authors: Slaper-Cortenbach
authors: Cell Therapy Facility, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Marcel P H
authors: MP
authors: van den Broek
authors: Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Razmara
authors: R
authors: Nizak
authors: Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Mattie H P
authors: MH
authors: van Rijen
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Roel A
authors: RA
authors: de Weger
authors: Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
authors: Wouter J A
authors: WJ
authors: Dhert
authors: Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.|MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors: Daniel B F
authors: DB
authors: Saris
mesh_terms: D000328:Adult; D001182:Arthroscopy; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D019902:Chondrocytes / Q000166:cytology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018895:Microsatellite Repeats / Q000235:genetics; D012038:Regeneration; D014182:Transplantation, Autologous; D016896:Treatment Outcome
keywords: Bone marrow stromal cells; Cellular therapy; Clinical translation; First in man; Tissue regeneration; chondrons