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Int J Mol Sci. 2019 Sep 2;20(17). pii: E4295. doi: 10.3390/ijms20174295.

The Role of Extracellular Matrix Expression, ERK1/2 Signaling and Cell Cohesiveness for Cartilage Yield from iPSCs.

Author information

1
Research Center for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstr. 200a, 69118 Heidelberg, Germany.
2
Center of Orthopaedic and Trauma Surgery, Heidelberg University Hospital, Schlierbacher Landstr. 200a, 69118 Heidelberg, Germany.
3
Research Center for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstr. 200a, 69118 Heidelberg, Germany. wiltrud.richter@med.uni-heidelberg.de.

Abstract

Current therapies involving chondrocytes or mesenchymal stromal cells (MSCs) remain inefficient in restoring cartilage properties upon injury. The induced pluripotent stem-cell (iPSC)-derived mesenchymal progenitor cells (iMPCs) have been put forward as a promising alternative cell source due to their high proliferation and differentiation potential. However, the observed cell loss during in vitro chondrogenesis is currently a bottleneck in establishing articular chondrocyte generation from iPSCs. In a search for candidate mechanisms underlying the low iPSC-derived cartilage tissue yield, global transcriptomes were compared between iMPCs and MSCs and the cell properties were analyzed via a condensation assay. The iMPCs had a more juvenile mesenchymal gene signature than MSCs with less myofibroblast-like characteristics, including significantly lower ECM- and integrin-ligand-related as well as lower α-smooth-muscle-actin expression. This correlated with less substrate and more cell-cell adhesion, impaired aggregate formation and consequently inferior cohesive tissue properties of the iMPC-pellets. Along lower expression of pro-survival ECM molecules, like decorin, collagen VI, lumican and laminin, the iMPC populations had significantly less active ERK1/2 compared to MSCs. Overall, this study proposes that this ECM and integrin-ligand shortage, together with insufficient pro-survival ERK1/2-activity, explains the loss of a non-aggregating iMPC sub-fraction during pellet formation and reduced survival of cells in early pellets. Enhancing ECM production and related signaling in iMPCs may be a promising new means to enrich the instructive microenvironment with pro-survival cues allowing to improve the final cartilage tissue yield from iPSCs.

KEYWORDS:

ERK1/2 signaling; cartilage regeneration; extracellular matrix; induced pluripotent stem cells; mesenchymal stromal cells

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