Abstract
Transplantation of adipose-derived mesenchymal stem cells (ASCs) induces tissue regeneration by accelerating the growth of blood vessels and nerve. However, mechanisms by which they accelerate the growth of nerve fibers are only partially understood. We used transplantation of ASCs with subcutaneous matrigel implants (well-known in vivo model of angiogenesis) and model of mice limb reinnervation to check the influence of ASC on nerve growth. Here we show that ASCs stimulate the regeneration of nerves in innervated mice's limbs and induce axon growth in subcutaneous matrigel implants. To investigate the mechanism of this action we analyzed different properties of these cells and showed that they express numerous genes of neurotrophins and extracellular matrix proteins required for the nerve growth and myelination. Induction of neural differentiation of ASCs enhances production of brain-derived neurotrophic factor (BDNF) as well as ability of these cells to induce nerve fiber growth. BDNF neutralizing antibodies abrogated the stimulatory effects of ASCs on the growth of nerve sprouts. These data suggest that ASCs induce nerve repair and growth via BDNF production. This stimulatory effect can be further enhanced by culturing the cells in neural differentiation medium prior to transplantation.
Highlights
Cell therapy has been proposed as an efficient method for regenerating injured nerves [1]
As early as 2 days after injury, peroneal functional index (PFI) [15] of the injured limbs of animals treated with mouse ASCs (mASCs) was greater comparing to negative controls (280.4 (288.2; 274.7), n = 84 vs. 2110.5 (2115.8; 2106.0), n = 84; p,0.001), and positive controls (2109.8 (2121.7; 2106.5), n = 84; p,0.001), indicating faster recovery of motor nerves exposed to an Adipose-derived stem cells (ASCs) (Figure 1A)
Despite peroneal function index (PFI) of mice treated with mASCs was greater compared to negative control group 7 days after injury (242.8 (248.0; 216.1), n = 84, vs. 265.2 (266.7; 264.5), n = 84, p#0.001) it did not differ from positive control group (244.0 (254.1; 237.9), n = 84, p = 0.075)
Summary
Cell therapy has been proposed as an efficient method for regenerating injured nerves [1]. Transplantation of Schwann cells or stem cells of various origins, which differentiate towards Schwann cell-like phenotype, stimulate peripheral nerve repair. Obtaining Schwann cells for autologous transplantation is highly traumatic and these cells are difficult to expand in vitro [3]. Adipose-derived stem cells (ASCs) can be obtained and expanded in vitro for use in autologous cell therapy. Transplanted ASCs stimulate blood vessel growth in vivo [4,5]. Nerve conduits seeded with ASCs differentiated towards Schwann-like cell phenotype and promote peripheral nerve repair. Mechanisms of ASC’s action on nerve regeneration are only partially understood. This can be addressed using in vivo models of nerve injury and growth in conjunction with determining gene expression patterns in the cells
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