Peripheral nerve regeneration has an intrinsic ability to regenerate and it depends on glial SCs to create a favorable environment that enhances nerve regeneration. Schwann cells (SCs) are key regulators of peripheral nerve regeneration and axonal myelination. Although SCs are an attractive therapeutic option for peripheral nerve injuries, there are several restrictions on their clinical application. Adipose derived stem cells (ASCs) represent an attractive source for cell therapies. When exposed to selective growth factors, they can acquire a SC-like phenotype (dASCs) expressing key SC markers and adopting a spindle-shape morphology. Neurotransmitters receptors such as GABA and Acetylcholine (ACh) are expressed during nervous system development and they contribute to SCs differentiation and myelin formation. Our group has demonstrated that Acetylcholine, via M2 muscarinic receptors, causes a reversible arrest of cell proliferation in SCs, increasing myelin proteins expression. dASCs also express muscarinic receptors. In rat model, M2 receptor activation causes a reversible arrest of the cell growth, without affecting cell survival. Moreover, its activation inhibits dASCs migration. M2 receptor stimulation also causes a significant decrease in neurotrophins expression, accompanied by a decreased release of proNGF and mNGF forms. The apoptotic proNGF isoform (25kDa) is strongly reduced after M2 receptor stimulation. Our data suggest that M2 receptors may be relevant for dASCs maturation and myelination, perhaps in a similar way to that observed in SCs.
The main aim of the present project will be to evaluate if muscarinic receptors activation may contribute also to human SC and dASCs proliferation and/or differentiation. These results may have a relevant impact on therapeutic treatment of human peripheral nerve injury.
For the first time we are able to characterise the role of Acetylcholine and muscarinic receptors in human Schwann cells and human dASCs. In order to find a new treatment to improve nerve regeneration and knowing the role of M2 receptor in rat model, it seems very interesting define how human cells respond to cholinergic stimuli.
The easiness of isolation and availability of ASCs, their differentiation into Schwann-like cells and ability to promote axonal regeneration are appealing for tissue engineering. Despite encouraging early reports for other neurotrasmitters, the true phenotype and function of dASCs after cholinergic stimuli remains to be fully established.
Our aims will be to assess the phenotypic and bioassay characteristics of human dASCs after cholinergic stimuli and define their applicability in the treatment of peripheral nerve injury.