title: Hyaluronan Is Crucial for Stem Cell Differentiation into Smooth Muscle Lineage.
abstract: Deciphering the extracellular signals that regulate SMC differentiation from stem cells is vital to further our understanding of the pathogenesis of vascular disease and for development of cell-based therapies and tissue engineering. Hyaluronan (HA) has emerged as an important component of the stem cell niche, however its role during stem cell differentiation is a complicated and inadequately defined process. This study aimed to investigate the role of HA in embryonic stem cell (ESC) differentiation toward a SMC lineage. ESCs were seeded on collagen-IV in differentiation medium to generate ESC-derived SMCs (esSMCs). Differentiation coincided with increased HA synthase (HAS) 2 expression, accumulation of extracellular HA and its assembly into pericellular matrices. Inhibition of HA synthesis by 4-methylumbelliferone (4MU), removal of the HA coat by hyaluronidase (HYAL) or HAS2 knockdown led to abrogation of SMC gene expression. HA activates ERK1/2 and suppresses EGFR signaling pathways via its principle receptor, CD44. EGFR inactivation coincided with increased binding to CD44, which was further augmented by addition of high molecular weight (HMW)-HA either exogenously or via HAS2 overexpression through adenoviral gene transfer. HMW-HA-stimulated esSMCs displayed a functional role in vascular tissue engineering ex vivo, vasculogenesis in a matrigel plug model and SMC accumulation in neointimal lesions of vein grafts in mice. These findings demonstrate that HAS2-induced HA synthesis and organization drives ESC-SMC differentiation. Thus, remodeling of the HA microenvironment is a critical step in directing stem cell differentiation toward a vascular lineage, highlighting HA as a potential target for treatment of vascular diseases. Stem Cells 2016;34:1225-1238.
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Russell M L
authors: RM
authors: Simpson
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Xuechong
authors: X
authors: Hong
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Mei Mei
authors: MM
authors: Wong
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Eirini
authors: E
authors: Karamariti
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Shirin Issa
authors: SI
authors: Bhaloo
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Derek
authors: D
authors: Warren
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China.
authors: Wei
authors: W
authors: Kong
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Yanhua
authors: Y
authors: Hu
authors: Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, United Kingdom.
authors: Qingbo
authors: Q
authors: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D000076002:Hyaluronan Synthases / Q000378:metabolism; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D058426:Neointima / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D015854:Up-Regulation
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D000076002:Hyaluronan Synthases; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Hyaluronan; Neointima; Smooth muscle cells; Stem cells; Vasculogenesis