Abstract
In the recent decade, embryonic stem cells (ESC) have emerged as an attractive cell source of smooth muscle cells (SMC) for vascular tissue engineering owing to their unlimited self-renewal and differentiation capacities. Despite their promise in therapy, their efficacy is still hampered by the lack of definitive SMC differentiation mechanisms and difficulties in successful trafficking of the ESC towards a site of injury or target tissue. Heat shock protein 47 (HSP47) is a 47-kDa molecular chaperone that is required for the maturation of various types of collagen and has been shown to be a critical modulator of different pathological and physiological processes. To date, the role of HSP47 on ESC to SMC differentiation or ESC chemotaxis is not known and may represent a potential molecular approach by which ESC can be manipulated to increase their efficacy in clinic. We provide evidence that HSP47 is highly expressed during ESC differentiation into the SMC lineage and that HSP47 reduction results in an attenuation of the differentiation. Our experiments using a HSP47 plasmid transfection system show that gene over-expression is sufficient to induce ESC-SMC differentiation, even in the absence of exogenous stimuli. Furthermore, HSP47 over-expression in ESC also increases their chemotaxis and migratory responses towards a panel of chemokines, likely via the upregulation of chemokine receptors. Our findings provide direct evidence of induced ESC migration and differentiation into SMC via the over-expression of HSP47, thus identifying a novel approach of molecular manipulation that can potentially be exploited to improve stem cell therapy for vascular repair and regeneration.
Highlights
The construction of vascular tissues to replace damaged and injured vessels is a fundamental strategy in development of new treatments for cardiovascular disease
Heat shock protein 47 (HSP47) is expressed during smooth muscle cells (SMC) differentiation Firstly, we wanted to investigate if HSP47 was expressed during the process of SMC differentiation from embryonic stem cells (ESC)
We provide the first evidence that HSP47 gene expression is significantly upregulated during the differentiation of ESC into SMC
Summary
The construction of vascular tissues to replace damaged and injured vessels is a fundamental strategy in development of new treatments for cardiovascular disease. Effective transdifferentiation of stem cells is likely to be highly dependent on their regulated chemotaxis, whether via the administration of exogenous factors or molecular programming of the stem cells. Chemokine receptors and their corresponding ligands have been established as key mediators of migration and trafficking in many cell types [9,10]. Our study suggests a putative role of HSP47 in enhancing the chemotaxis and differentiation of ESC into SMC, indicating a novel mechanism of molecular manipulation that can be exploited to improve stem cell therapy for vascular repair and regeneration
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