Abstract
Thermoresponsive cell culture plates release cells as confluent living sheets in response to small changes in temperature, with recovered cell sheets retaining functional extracellular matrix proteins and tight junctions, both of which indicate formation of intact and functional tissue. Our recent studies demonstrated that cell sheets are highly effective in promoting mouse submandibular gland (SMG) cell differentiation and recovering tissue integrity. However, these studies were performed only at early time points and extension of the observation period is needed to investigate duration of the cell sheets. Thus, the goal of this study was to demonstrate that treatment of wounded mouse SMG with cell sheets is capable of increasing salivary epithelial integrity over extended time periods. The results indicate that cell sheets promote tissue organization as early as eight days after transplantation and that these effects endure through Day 20. Furthermore, cell sheet transplantation in wounded SMG induces a significant time-dependent enhancement of cell polarization, differentiation and ion transporter expression. Finally, this treatment restored saliva quantity to pre-wounding levels at both eight and twenty days post-surgery and significantly improved saliva quality at twenty days post-surgery. These data indicate that cell sheets engineered with thermoresponsive cell culture plates are useful for salivary gland regeneration and provide evidence for the long-term stability of cell sheets, thereby offering a potential new therapeutic strategy for treating hyposalivation.
Highlights
Hyposalivation is the reduction of salivary flow contributing to oral microbial infections that impairs activities of daily living [1]
Our previous study showed that cell sheets promote wound healing at eight days, as indicated by organized formation of glandular tissue with minimal fibrosis in a wounded submandibular gland (SMG) mouse model [49]
We investigated whether treatment of wounded mouse SMG with cell sheets promotes wound healing twenty days post-surgery using hematoxylin-eosin staining
Summary
Hyposalivation is the reduction of salivary flow contributing to oral microbial infections that impairs activities of daily living (e.g., speaking, chewing and swallowing) [1]. Current treatments for hyposalivation are limited to the muscarinic receptor agonists pilocarpine and cevimeline that induce saliva secretion from residual acinar cells [4] and the use of saliva substitutes [5]. In light of the above, several alternative treatments for hyposalivation, such as surgical transplantation of stem cells, use of bioengineered organ-germs, growth factor delivery and scaffold implantation, are being developed to improve these patients’ quality of life [8,9,10]. Stem cell-mediated treatment is limited by cell survival and the relatively short effectiveness of growth factor secreted by stem cells [12,13]. In terms of growth factors, several studies demonstrated that they maximize ex vivo tissue expansion by regulating salivary gland cell proliferation, regeneration and differentiation [14,15]
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