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Title: Schwann cell-like differentiated adipose-derived stem cells : in vivo applications and future perspectives for nerve regeneration
Author: Di Summa, Pietro Giovanni
ISNI:       0000 0004 2737 3819
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Traumatic injuries resulting in peripheral nerve lesions often require a graft to bridge the gap. Although autologous nerve graft is still the first choice strategy in reconstructions, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to create a favourable environment for nerve regeneration. Among adult stem cells, adipose-derived stem cells (ASC) are a useful tool in regenerative medicine as they can be induced towards multiple mesodermal and nonmesodermal lineages, being recently differentiated into cells showing Schwann cell-like morphology, glial cell markers and increased neurotrophic potential. The first two chapters of this work describe in vivo applications of Schwann cell-like differentiated ASC (dASC), seeded into biodegradable nerve guides made of fibrin, investigating both brief (2 weeks) and long (4 months) term effects on the regenerating nerves. Comparison was carried out with similarly differentiated bone marrow mesenchymal stem cells (dMSC), Schwann cells (SC)and empty fibrin conduits, as well as with autologous nerve grafts. Regeneration was evaluated in a 1cm gap total axotomy sciatic nerve injury model on rats. Results showed that dASC could improve regeneration distance in a similar manner to other regenerative cells inthe brief term. This effect was maintained and strengthened in the long term, where nerve morphology, spinal motoneurons regeneration, protection from muscle atrophy and electrophysiological performances of regenerated nerves were analysed. dASC positive effects lasted in the long term with functional results comparable to the autologous nerve grafts, which served as controls. The third chapter focuses on the possibility to further improve dASC regenerative performances using fibronectin and laminin, two key extracellular matrix (ECM) molecules involved in nerve regeneration, with the future aim to optimize cell host, directional cues and neurotrophism of tissue engineered conduits. Fibronectin and laminin protected dASC from stress-induced cell death in vitro, significantly increasing cell adhesion and viability. Laminin significantly improved neurotrophic properties of dASC enhancing neurite outgrowth of both primary sensory neurons and NG108-15 neurons co-cultured with dASC, suggesting a further activation of the neurotrophic effect of dASC by ECM molecules. These improved effects were increased when a direct contact was established between the laminin substrate, dASC and neurons, suggesting a primary role of laminin in contact signalling, finally boosting the neurotrophic potential of dASC. Further studies will be needed to clarify the interactions between dASC and the complexniche of peripheral nerve regeneration, including the ECM molecules. However, the neurotrophic potential of dASC expressed in both in vitro and in vivo experiments opens wide perspectives in tissue engineering applications among new methods to enhance peripheral nerve repair.
Supervisor: Terenghi, Giorgio Sponsor: Department of Plastic ; Reconstructive surgery ; University Hospital of Lausanne ; CH ; Swiss National Found for Scientific Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: adipose-derived stem cells ; regenerative cells ; peripheral nerve regeneration ; extracellular matrix ; sciatic nerve ; nerve conduits ; fibrin