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Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis

Occhetta, P and Pigeot, S and Halleux, Christine and Rasponi, M and Dasen, B and Ullrich, Thomas and Kramer, Ina and Guth-Gundel, Sabine and Barbero, A and Martin, I (2018) Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis. Proceedings of the National Academy of Sciences of the United States of America, 115 (18). pp. 4625-4630. ISSN 10916490

Abstract

It is generally accepted that adult human bone marrow-derived mesenchymal stromal cells (hMSCs) are default committed toward osteogenesis. Even when induced to chondrogenesis, hMSCs typically form hypertrophic cartilage that undergoes endochondral ossification. Because embryonic mesenchyme is obviously competent to generate phenotypically stable cartilage, it is questioned whether there is a correspondence between mesenchymal progenitor compartments during development and in adulthood. Here we tested whether forcing specific early events of articular cartilage development can program hMSC fate toward stable chondrogenesis. Inspired by recent findings that spatial restriction of bone morphogenetic protein (BMP) signaling guides embryonic progenitors toward articular cartilage formation, we hypothesized that selective inhibition of BMP drives the phenotypic stability of hMSC-derived chondrocytes. Two BMP type I receptor-biased kinase inhibitors were screened in a microfluidic platform for their time- and dose-dependent effect on hMSC chondrogenesis. The different receptor selectivity profile of tested compounds allowed demonstration that transient blockade of both ALK2 and ALK3 receptors, while permissive to hMSC cartilage formation, is necessary and sufficient to maintain a stable chondrocyte phenotype. Remarkably, even upon compound removal, hMSCs were no longer competent to undergo hypertrophy in vitro and endochondral ossification in vivo, indicating the onset of a constitutive change. Our findings demonstrate that adult hMSCs effectively share properties of embryonic mesenchyme in the formation of transient but also of stable cartilage. This opens potential pharmacological strategies to articular cartilage regeneration and more broadly indicates the relevance of developmentally inspired protocols to control the fate of adult progenitor cell systems.

Item Type: Article
Keywords: Articular cartilage BMPs Developmental engineering Mesenchymal stromal cells Microfluidics
Date Deposited: 06 Jun 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/34846

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