Abstract
Temperature-responsive polymer grafted tissue culture dishes release cells as confluent living sheets in response to small changes in temperature, with recovered cell sheets retaining cell–cell communications, functional extracellular matrices and tissue-like behaviors. These features promote tissue regeneration and improve transplantation efficacy in various tissues including cartilage, heart, kidney, liver, endometrium, cornea, middle ear, periodontium, and esophageal living sheet transplants. However, the functional effects of cell sheets for salivary gland regeneration to treat hyposalivation have not yet been studied. Thus, the present study aims to both establish the viability of thermoresponsive cell sheets for use in salivary glands and then explore the delivery option (i.e., single vs. multiple layers) that would result in the most complete tissue growth in terms of cell differentiation and recovered tissue integrity. Results indicate that single cell sheets form polarized structures that maintain cell–cell junctions and secretory granules in vitro while layering of two-single cell sheets forms a glandular-like pattern in vitro. Moreover, double layer cell sheets enhance tissue formation, cell differentiation and saliva secretion in vivo. In contrast, single cell sheets demonstrated only modest gains relative to the robust growth seen with the double layer variety. Together, these data verify the utility of thermoresponsive cell sheets for use in salivary glands and indicates the double layer form to provide the best option in terms of cell differentiation and recovered tissue integrity, thereby offering a potential new therapeutic strategy for treating hyposalivation.
Highlights
These results demonstrate that Submandibular gland (SMG) are capable of forming polarized cell sheets in vitro when cultured on thermoresponsive plates
We detected microvilli-like structures on the apical side of the cell sheet (Fig. 2a) and secretory granules (SG) located towards the apical membrane (Fig. 2b) similar to mouse native SMG specimen (Fig. 2c)
Transplants),[35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52] they can be applied in salivary glands to promote cell differentiation and tissue integrity
Summary
Xerostomia is the sensation of having a dry mouth and is commonly associated with a reduction of saliva flow (i.e., hyposalivation).[1,2] Several conditions have been linked to hyposalivation including the following: (a) Sjögren’s syndrome, the second most common rheumatic disease after rheumatoid arthritis affecting more than 4 million people in the US,[3,4] (b) γirradiation therapy that affects ~60,000 head and neck cancer patients in the US,[5] (c) genetic diseases including lacrimoauriculodentodigital syndrome, autosomal dominant salivary gland hypoplasia, salivary glands agenesis and chronic recurrent sialadenitis that are less frequent but cause a significant burden in many patients,[6,7] and (d) side effects of more than 50 commonly used medications.[8,9] Causes of hyposalivation are seen to be multiple but with presenting symptoms typically including unresolved inflammation and/or impaired tissue homeostasis and regeneration.[10]. Current treatments for hyposalivation include the use of artificial saliva and secretory agonists such as pilocarpine and cevimeline; they provide only temporary relief and result in significant side effects, respectively.[13,14] In the search for novel alternatives, some promise has been shown with the use of gene therapy for aquaporin 1 (AQP1) directed to improve water secretion in ductal cells This therapy has proven to be somewhat successful in addressing hyposalivation, it still does not offer a replacement for salivary proteins.[15,16] Other studies pursuing alternative treatments include the use a variety of scaffolds using natural (e.g., fibrin hydrogel,[17,18,19] collagen,[20] hyaluronic acid,[21] silk,[22] and alginate23) as well as synthetic polymers (e.g., poly-glycolic acid, poly-lactic acid, and polyethylene glycol24–26), all of which have been shown to promote salivary gland regeneration, both in vitro and in vivo. Despite the shortcomings of stem cells noted above, this technology remains very attractive due to the possibility of providing for a steady stream of host tissue
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