Long-term expansion, enhanced chondrogenic potential, and suppression of endochondral ossification of adult human MSCs via WNT signaling modulation.
Mesenchymal stem cells (MSCs) are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair.
Department of Orthopaedics, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands.
Roberto
R
Narcisi
Department of Orthopaedics, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands; Section of Veterinary Clinical Sciences, School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Mairéad A
MA
Cleary
Section of Veterinary Clinical Sciences, School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Pieter A J
PA
Brama
Department of Internal Medicine, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands.
Martin J
MJ
Hoogduijn
Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands.
Nesrin
N
Tüysüz
Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands. Electronic address: d.tenberge@erasmusmc.nl.
Derk
D
ten Berge
Department of Orthopaedics, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands; Department of Otorhinolaryngology, Erasmus MC, University Medical Center, 3015 CN Rotterdam, the Netherlands. Electronic address: g.vanosch@erasmusmc.nl.
Gerjo J V M
GJ
van Osch
D000368:Aged; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D020219:Chondrogenesis / Q000187:drug effects; D004330:Drosophila; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D060449:Wnt Signaling Pathway / Q000187:drug effects; D060509:Wnt3A Protein / Q000378:metabolism / Q000494:pharmacology
D060509:Wnt3A Protein; D016222:Fibroblast Growth Factor 2