Abstract
Head and neck cancer is often diagnosed at advanced stages, and surgical resection with wide margins is generally indicated, despite this treatment being associated with poor postoperative quality of life (QOL). We have previously reported on the therapeutic effects of skeletal muscle-derived multipotent stem cells (Sk-MSCs), which exert reconstitution capacity for muscle-nerve-blood vessel units. Recently, we further developed a 3D patch-transplantation system using Sk-MSC sheet-pellets. The aim of this study is the application of the 3D Sk-MSC transplantation system to the reconstitution of facial complex nerve-vascular networks after severe damage. Mouse experiments were performed for histological analysis and rats were used for functional examinations. The Sk-MSC sheet-pellets were prepared from GFP-Tg mice and SD rats, and were transplanted into the facial resection model (ST). Culture medium was transplanted as a control (NT). In the mouse experiment, facial-nerve-palsy (FNP) scoring was performed weekly during the recovery period, and immunohistochemistry was used for the evaluation of histological recovery after 8 weeks. In rats, contractility of facial muscles was measured via electrical stimulation of facial nerves root, as the marker of total functional recovery at 8 weeks after transplantation. The ST-group showed significantly higher FNP (about three fold) scores when compared to the NT-group after 2–8 weeks. Similarly, significant functional recovery of whisker movement muscles was confirmed in the ST-group at 8 weeks after transplantation. In addition, engrafted GFP+ cells formed complex branches of nerve-vascular networks, with differentiation into Schwann cells and perineurial/endoneurial cells, as well as vascular endothelial and smooth muscle cells. Thus, Sk-MSC sheet-pellet transplantation is potentially useful for functional reconstitution therapy of large defects in facial nerve-vascular networks.
Highlights
Cancer of the head and neck area are often diagnosed at advanced stages, and wide surgical resection is generally indicated for curative purpose
A wide range of nerve-vascular networks, including the facial nerves, tend to be removed with the lesion and this leads to various symptoms of nerve deficiency, such as difficulties in talking, eating or drinking, as well as drooling and muscle twitching, because the facial area includes special sense organs, sensitive muscular systems and various glandular organs; damage reduces postoperative quality of life (QOL)
We have reported on the therapeutic effects of skeletal muscle-derived multipotent stem cells (Sk-MSCs), which have a synchronized reconstitution capacity for muscle-nerve-blood vessel units [10,11,12]
Summary
Cancer of the head and neck area are often diagnosed at advanced stages, and wide surgical resection is generally indicated for curative purpose. Facial neural networks are highly complex relative to other areas of the body. Application of artificial neural tubes has been attempted as an alternative treatment [1, 2], but the results remain unsatisfactory. Transplantation of stem cells, such as bone marrow mesenchymal stem cells [4, 5], adipose-derived stem cells [6, 7], Schwann-like mesenchymal stem cells [8], and dental pulp cells [9], has been attempted with artificial neural tubes. The therapeutic effects are limited, because of difficulties in regenerating the complex networks of the facial nerve-vascular system in the large deficits with long gaps. It is difficult to bridge multiple nerve branches using nerve grafts or artificial conduits
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