Abstract
Loss of vital functions in the somatic motor and sensory nervous systems can be induced by severe peripheral nerve transection with a long gap following trauma. In such cases, autologous nerve grafts have been used as the gold standard, with the expectation of activation and proliferation of graft-concomitant Schwann cells associated with their paracrine effects. However, there are a limited number of suitable sites available for harvesting of nerve autografts due to the unavoidable sacrifice of other healthy functions. To overcome this problem, the potential of skeletal muscle-derived multipotent stem cells (Sk-MSCs) was examined as a novel alternative cell source for peripheral nerve regeneration. Cultured/expanded Sk-MSCs were injected into severely crushed sciatic nerve corresponding to serious neurotmesis. After 4 weeks, engrafted Sk-MSCs preferentially differentiated into not only Schwann cells, but also perineurial/endoneurial cells, and formed myelin sheath and perineurium/endoneurium, encircling the regenerated axons. Increased vascular formation was also observed, leading to a favorable blood supply and waste product excretion. In addition, engrafted cells expressed key neurotrophic and nerve/vascular growth factor mRNAs; thus, endocrine/paracrine effects for the donor/recipient cells were also expected. Interestingly, skeletal myogenic capacity of expanded Sk-MSCs was clearly diminished in peripheral nerve niche. The same differentiation and tissue reconstitution capacity of Sk-MSCs was sufficiently exerted in the long nerve gap bridging the acellular conduit, which facilitated nerve regeneration/reconnection. These effects represent favorable functional recovery in Sk-MSC-treated mice, as demonstrated by good corduroy walking. We also demonstrated that these differentiation characteristics of the Sk-MSCs were comparable to native peripheral nerve-derived cells, whereas the therapeutic capacities were largely superior in Sk-MSCs. Therefore, Sk-MSCs can be a novel/suitable alternative cell source for healthy nerve autografts.
Highlights
Traumatic peripheral nerve injury can be caused by mechanical trauma such as penetration, crush, traction and lacerations, and may be associated with long bone fractures, such as those occurring in traffic accidents [1,2]
At 4 weeks after transplantation, engrafted skeletal muscle-derived multipotent stem cells (Sk-MSCs), bone marrow stromal cells (BMSCs) and sciatic nerve-derived cells (SNDCs) were detectable as GFP+ tissues under fluorescence stereomicroscopy
Stronger and widespread emissions could be seen after skeletal muscle-derived multipotent stem cells (SkMSCs) transplantation than in BMSC and SNDC, with the expectation of greater engraftment ability as a constant trend throughout the experiment (Fig. 1F–H)
Summary
Traumatic peripheral nerve injury can be caused by mechanical trauma such as penetration, crush, traction and lacerations, and may be associated with long bone fractures, such as those occurring in traffic accidents [1,2]. These injuries are classified according to two international standards: the Seddon and the Sunderland [3,4]. It appears clear that acellular conduits do not facilitate nerve regeneration across long gaps [5]
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