title: Footprint-free human induced pluripotent stem cells from articular cartilage with redifferentiation capacity: a first step toward a clinical-grade cell source.
abstract: Human induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine; however, clinical applications of iPSCs are restricted because of undesired genomic modifications associated with most reprogramming protocols. We show, for the first time, that chondrocytes from autologous chondrocyte implantation (ACI) donors can be efficiently reprogrammed into iPSCs using a nonintegrating method based on mRNA delivery, resulting in footprint-free iPSCs (no genome-sequence modifications), devoid of viral factors or remaining reprogramming molecules. The search for universal allogeneic cell sources for the ACI regenerative treatment has been difficult because making chondrocytes with high matrix-forming capacity from pluripotent human embryonic stem cells has proven challenging and human mesenchymal stem cells have a predisposition to form hypertrophic cartilage and bone. We show that chondrocyte-derived iPSCs can be redifferentiated in vitro into cartilage matrix-producing cells better than fibroblast-derived iPSCs and on par with the donor chondrocytes, suggesting the existence of a differentiation bias toward the somatic cell origin and making chondrocyte-derived iPSCs a promising candidate universal cell source for ACI. Whole-genome single nucleotide polymorphism array and karyotyping were used to verify the genomic integrity and stability of the established iPSC lines. Our results suggest that RNA-based technology eliminates the risk of genomic integrations or aberrations, an important step toward a clinical-grade cell source for regenerative medicine such as treatment of cartilage defects and osteoarthritis.
authors.affiliation: Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Cellectis Bioresearch, Gothenburg, Sweden; Division of Biotechnology/IFM, Linköping University, Linköping, Sweden; Cell Therapy Catapult Limited, London, United Kingdom.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Boreström
authors.forename: Stina
authors.initials: S
authors.lastname: Simonsson
authors.forename: Lars
authors.initials: L
authors.lastname: Enochson
authors.forename: Narmin
authors.initials: N
authors.lastname: Bigdeli
authors.forename: Camilla
authors.initials: C
authors.lastname: Brantsing
authors.forename: Catharina
authors.initials: C
authors.lastname: Ellerström
authors.forename: Johan
authors.initials: J
authors.lastname: Hyllner
authors.forename: Anders
authors.initials: A
authors.lastname: Lindahl
mesh_terms: D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism
keywords: Chondrocytes; Chondrogenesis; Induced pluripotency; Induced pluripotent stem cells; Reprogramming; mRNA