Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44/ERK/SOX-9 pathway

[Display omitted] Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the cho...

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Published in:	Acta biomaterialia 2018-01, Vol.66, p.224-237
Main Authors:	Wu, Shun-Cheng, Chen, Chung-Hwan, Wang, Jyun-Ya, Lin, Yi-Shan, Chang, Je-Ken, Ho, Mei-Ling
Format:	Article
Language:	eng
Subjects:	Adipose-derived stem cells (ADSCs) Agglomeration Aggrecan CD44 antigen CD44 clustering Cell aggregation Chondrogenesis Clustering Collagen (type II) Deposition ERK/SOX-9 Extracellular matrix Extracellular signal-regulated kinase Gene expression Hyaluronan Hyaluronan (HA) Hyaluronic acid Inhibition Mathematical analysis Matrix methods Molecular chains Molecular weight Molecular weight (Mw) Phosphorylation Signal transduction Stem cells Studies Surgical implants
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Summary:	[Display omitted] Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the chondrogenic niche. The aim of this study is to investigate the optimal HA molecular weight (Mw) for chondrogenesis of ADSCs and the detailed mechanism. In this study, we investigated the relationships among HA Mw, CD44 clustering, and the extracellular signal-regulated kinase (ERK)/SOX-9 pathway during chondrogenesis of ADSCs. Human ADSCs (hADSCs) and rabbit ADSCs (rADSCs) were isolated and expanded. Chondrogenesis was induced in rADSCs by culturing cells in HA-coated wells (HA Mw: 80 kDa, 600 kDa and 2000 kDa) and evaluated by examining cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and sulfated glycosaminoglycan (sGAG) deposition in vitro. Cartilaginous tissue formation in vivo was confirmed by implanting HA/rADSCs into joint cavities. CD44 clustering, ERK phosphorylation, SOX-9 expression and SOX-9 phosphorylation in cultured hADSCs were further evaluated. Isolated and expanded rADSCs showed multilineage potential and anchorage-independent growth properties. Cell aggregation, chondrogenic gene expression, and sGAG deposition increased with increasing HA Mw in rADSCs. The 2000 kDa HA had the most pronounced chondrogenic effect on rADSCs in vitro, and implanted 2000 kDa HA/rADSCs exhibited marked cartilaginous tissue formation in vivo. CD44 clustering and cell aggregation of hADSCs were enhanced by an increase in HA Mw. In addition, higher HA Mws further enhanced CD44 clustering, ERK phosphorylation, and SOX-9 expression and phosphorylation in hADSCs. Inhibiting CD44 clustering in hADSCs reduced HA-induced chondrogenic gene expression. Inhibiting ERK phosphorylation also simultaneously attenuated HA-induced SOX-9 expression and phosphorylation and chondrogenic gene expression in hADSCs. Our results indicate that HA initiates ADSC chondrogenesis and that higher Mw HAs exhibit stronger effects, with 2000 kDa HA having the strongest effect. These effects may be mediated through increased CD44 clustering and the ERK/SOX-9 signaling pathway. HA-based biomaterials have been studied in stem cell-based articular cartilage tissue engineering. However, little is known about the optimal HA size for stem cell chondrogenesis and the mechanism o
ISSN:	1742-7061 1878-7568