Tacrolimus-Induced Neurotrophic Differentiation of Adipose-Derived Stem Cells as Novel Therapeutic Method for Peripheral Nerve Injury

Abstract

Peripheral nerve injuries (PNIs) are frequent traumatic injuries across the globe. Severe PNIs result in irreversible loss of axons and myelin sheaths and disability of motor and sensory function. Schwann cells can secrete neurotrophic factors and myelinate the injured axons to repair PNIs. However, Schwann cells are hard to harvest and expand in vitro, which limit their clinical use. Adipose-derived stem cells (ADSCs) are easily accessible and have the potential to acquire neurotrophic phenotype under the induction of an established protocol. It has been noticed that Tacrolimus/FK506 promotes peripheral nerve regeneration, despite the mechanism of its pro-neurogenic capacity remains undefined. Herein, we investigated the neurotrophic capacity of ADSCs under the stimulation of tacrolimus. ADSCs were cultured in the induction medium for 18 days to differentiate along the glial lineage and were subjected to FK506 stimulation for the last 3 days. We discovered that FK506 greatly enhanced the neurotrophic phenotype of ADSCs which potentiated the nerve regeneration in a crush injury model. This work explored the novel application of FK506 synergized with ADSCs and thus shed promising light on the treatment of severe PNIs.

Hypoxic culture of umbilical cord mesenchymal stem cell-derived sEVs prompts peripheral nerve injury repair

“…Peripheral nerve injury is a traumatic intractable condition with a high rate of incidence. Currently, the main focus is on the PNI and treatments used to repair and regenerate nerve tissue and reduction of neuroinflammation, as a result, creating a beneficial micro-environment for neurogenesis and axonal regeneration ( Li F. et al, 2019 ; Yao et al, 2021 ). To date, great efforts have been made by researchers, but the effects of PNI treatment are still limited.…”

Experimental study on the repair of peripheral nerve injuries via simultaneously coapting the proximal and distal ends of peripheral nerves to the side of nearby intact nerves

“…Cut, pull and compression induced peripheral nerve injuries can bring about motor, sensory and nutritional dysfunction in the innervated area, and patients may be disabled as a result of delayed treatment ( 13 , 14 ). The clinical treatment effect for a large segmental peripheral nerve defect is poor, which has become a thorny problem for orthopedic doctors ( 15 , 16 ).…”

Implantation of a nerve protector embedded with human GMSC-derived Schwann-like cells accelerates regeneration of crush-injured rat sciatic nerves

“…Accumulating evidence has indicated that Schwann-like cells induced from different types of stem cells, including embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), and various multipotent postnatal stem cells, represent important alternative sources of Schwann cells, among which mesenchymal stem/stromal cells (MSCs) readily isolated from a variety of tissues, such as bone marrow, skin, adipose, umbilical cord, and dental tissues, are the major source of Schwann-like cells for cell-based therapy of PNIs [ 33 ]. However, several limitations exist in differentiating MSCs into Schwann-like cells, such as the requirement of special induction medium, the time-consuming process (usually taking 2 ~ 3 weeks in special induction conditions) [ 48 ], the variation in the induction efficiency, and the phenotypic instability of MSC-derived Schwann-like cells, etc. [ 33 , 49 ].…”

“…[ 33 , 49 ]. In recent years, various approaches have been developed to promote induction of MSCs into Schwann-like cells, particularly the use of certain small molecules or growth factors [ 48 , 50 ] and engineered substrates or scaffolds such as graphene oxide substrate [ 51 ], 3D-printed polycaprolactone/polypyrrole (PCL/PPy) conductive scaffold [ 52 ], 3D-printed bionic polycaprolactone (PCL) polymer scaffold [ 53 ], and aligned nanofibers [ 54 ]. Consistent with our recent studies [ 37 ], we, herein, have also demonstrated that GMSCs could directly and rapidly convert into Schwann-like cells when they were encapsulated in methacrylated 3D-collagen hydrogel and cultured under the regular MSC culture medium without the additional introduction of special nutritional and growth factor supplements (Fig.…”