Long-term expansion, enhanced chondrogenic potential, and suppression of endochondral ossification of adult human MSCs via WNT signaling modulation

Stem Cell Reports
Roberto NarcisiG J V M van Osch

Abstract

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.

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Citations

Nov 13, 2015·Tissue Engineering. Part B, Reviews·Gun-Il Im
Dec 22, 2015·Osteoarthritis and Cartilage·Mairéad A ClearyGerjo J V M van Osch
Jul 6, 2016·Frontiers in Surgery·James HoltonMartin Snow
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Sep 4, 2018·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Andrea LolliGerjo J V M van Osch
Dec 12, 2018·Tissue Engineering. Part a·Ellen Wilhelmina van GeffenPeter Mario van der Kraan
May 23, 2019·Journal of Tissue Engineering and Regenerative Medicine·Benjamin L LarsonLisa E Freed
Mar 29, 2019·Biofabrication·J LehmannG J van Osch
May 27, 2020·Journal of Cellular Physiology·Shirin TavakoliAdel Naimi
Feb 27, 2018·Frontiers in Bioengineering and Biotechnology·Aleksandra Leszczynska, J Mary Murphy
Jul 28, 2020·Frontiers in Bioengineering and Biotechnology·Chantal VoskampRoberto Narcisi
Apr 19, 2018·Proceedings of the National Academy of Sciences of the United States of America·Paola OcchettaIvan Martin
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Jul 31, 2021·Journal of Biomaterials Science. Polymer Edition·Samuel Ogbeide Ebhodaghe

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Methods Mentioned

BETA
flow cytometry
biopsies
FCS
PCR

Software Mentioned

Primer Express
NIH ImageJ
Quantum FX μCT
BD FACSDiva

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