Different Roles Played by Adipose-Derived Stem Cells in Peripheral Nerve Regeneration: State of the Art

Peripheral nerve injury is commonly attributable to traffic and industrial accidents, natural disasters, and war damage. Destruction of nerve fibers results in denervation of targeted muscles, which undergo progressive loss of function and atrophy as well: these conditions follow account for nearly $150 billion in annual health care spending in the United States [1,2].

A recent original article shows that Polyethylene Glycol (PEG) improves results of peripheral nerve microsuturing, with no need of Bittner's protocol.

This interesting, perspective, experimental study focused on regeneration of sciatic nerve, and on the PEG's role in enhancing sciatic nerve restoration after PNI, resulting into histologically demonstrated prevention of Wallerian degeneration, partial prevention of muscular atrophy and acceleration of recovery after sharp transections.

Behavioral assessment included both sensory feedback and motion control (Sciatic Function Index), with significant clinical improvement, while in vivo electrophysiology, involving the recording of compound muscle action potentials of the gastrocnemius muscle, showed higher peak values in rats treated with PEG compared to those in which standard sutures without PEG were performed. Last but not least, the authors focuses on the importance of building and enhancing a “pro-regenerative microenvironment” in order to concentrate specific tissue growth factors in damaged tissues, which can currently be considered a hot topic in regenerative surgery [3].

Different therapeutic approaches have been proposed for PNI, such as micro-sutures, synthetic or autologous conduits and autologous nerve grafts, which is preferred in short gaps injuries [4]. However, new strategies and research fields are debated about nervous tissue regeneration. Experimental studies published during last years show an increase of interest on Adipose derived stem cells (ASCs) in many fields, mainly because they can be easily harvested and have multilineage differentiation potential, can undergo effective expansion within weeks, can be obtained in a noninvasive manner and currently accesible at the point-of-care due to significant technological development.

The use of different heterologous substances or materials (such as PEG) in peripheral nerve regeneration have been proposed, and, moreover, as supports for ASCs action: in a recent study has been demonstrated the efficacy of polycaprolactone (PCL) with addition of adipose stem in repairing a 6 mm surgically ablated peripheral nerve, through mechanism wich are still not clear, but an increase in levels of S100 (Schwann cell marker) expression was observed [5].

It has been demonstrated as well that the ASC‐Exosomes (small membrane vesicles with a diameter of 50–150 nm) significantly improve peripheral nerve regeneration via optimizing Schwann Cells function and thereby represent an effective perspective in nerve tissue engineering [6]. It seems that implanted ASCs could improve the microenvironment of ANA (acellular nerve allograft) through secretion of neurotrophins and growth factors such as NGF (Nerve Growth Factor), BDNF (Brain-derived neurotrophic factor), CNTF (Ciliary neurotrophic factor), GDNF (glial-derived neurotrophic factor), and TGF-β that can induce axonal elongation. The genes of NGF, GDNF, and BDNF were persistently expressed after integrating neural differentiated ADSCs into ANM [7].

Other data demonstrated that the systemic administration of ALCAR (acetyl-l-carnitine) enhanced ASC-transplanted nerve allograft regenerative properties and resulting peripheral nerve regeneration which, again, according to another study, seems related to an interaction between ASCs, regenerative axons (Schwann Cells) and the ability to secrete neurotrophic factors (such as NGF, GDNF, and BDNF) [8].

About muscular atrophy, an investigation is suggestive that an ASC injection into denervated muscle post‐operatively is able to delay the onset of atrophy [9].

Beside, recent rodent studies have shown that ASCs promote muscle mass retention after PNI when administered into the denervated muscle [10,11].

However, alongside these enormous advantages about effects of ASCs on PNI in enhancing a good microenvironment for nervous tissue regeneration (any reconstructive surgical technique is used), producing growth factors and stimulating Schwann cells proliferation and their relative ease of use, some concern still remains. The low survival rate and retention of transplanted ASCs limits their therapeutic potential [12] and the harmful microenvironment of injured tissues makes ASCs survival difficult, whereas oxidative stress, energy failure and inflammatory response can lead to apoptosis [13]. Therefore, any approach that enhances survival and retention capacity of ASCs may improve the nerve regeneration process and be consequential to functional recovery.

Finally, safety in the use of stem-cells therapies is still a huge and debated argument in literature, and an univocal consent on their clinical applications, treatments and harvesting is currently not available, not least due to the differences in stem-cells regulations between various countries.

Further experimental studies are needed to better understand the molecular and cellular mechanisms induced by the use of stem cells in PNI, and, in order to propose their systematic use as adjuvants of different surgical techniques, standardization of therapeutic protocols and materials used in peripheral nerve repair is required.

DECLARATION OF INTEREST

The authors report no conflicts of interest.