Cell-free therapy based on extracellular vesicles: a promising therapeutic strategy for peripheral nerve injury

Abstract

Peripheral nerve injury (PNI) is one of the public health concerns that can result in a loss of sensory or motor function in the areas in which injured and non-injured nerves come together. Up until now, there has been no optimized therapy for complete nerve regeneration after PNI. Exosome-based therapies are an emerging and effective therapeutic strategy for promoting nerve regeneration and functional recovery. Exosomes, as natural extracellular vesicles, contain bioactive molecules for intracellular communications and nervous tissue function, which could overcome the challenges of cell-based therapies. Furthermore, the bioactivity and ability of exosomes to deliver various types of agents, such as proteins and microRNA, have made exosomes a potential approach for neurotherapeutics. However, the type of cell origin, dosage, and targeted delivery of exosomes still pose challenges for the clinical translation of exosome therapeutics. In this review, we have focused on Schwann cell and mesenchymal stem cell (MSC)-derived exosomes in nerve tissue regeneration. Also, we expressed the current understanding of MSC-derived exosomes related to nerve regeneration and provided insights for developing a cell-free MSC therapeutic strategy for nerve injury.

Keywords: Cell-free-based treatment; Exosomes; Extracellular vesicle; Mesenchymal stromal cells; Nerve regeneration; Peripheral neve injury.

Fig. 1

Illustrating exosome contents that promote axon regeneration through the PI3/AKT signaling pathway. Schwann cell-derived exosomes released from different phenotypic Schwann cells, like mature SCs and repair SCs, carry different cargoes that influence their functions. For example, repair SC-derived exosomes exhibit axonal regeneration after nerve injury due to their containing miRNA-21. miRNA-21 can cause the downregulation of phosphatase and tensin homolog (PTEN) and consequently the activation of phosphoinositide 3-kinase (PI3K) in the neurons. Also, SC-derived exosomes can inhibit neuron apoptosis and increase cell viability. On the other hand, exosomes derived from mature myelinating SCs cannot promote axonal regeneration and also inhibit SC migration

Fig. 2

Novel strategies of MSC-derived exosomes for curing nerve injury. MSCs can be isolated from bone marrow, adipose tissue, endometrium tissues, the umbilical cord, and the dental pulp. Their exosomes can regulate nerve-related cellular functions. MSC-derived exosomes are able to modulate neuroinflammation and immune cell reactions, neuroprotection, angiogenesis, and axonal regrowth and remyelination

Fig. 3

Diagram illustrates how MSC-derived exosomes can regulate expression of miRNA and activate PI3K/Akt, which induce activation of the PI3/AKT signaling pathway in neural cells, leading to promotion of nerve regeneration

Fig. 4

MSC-derived exosomes exhibit immunomodulatory and anti-inflammatory effects, which decrease nerve tissue damage. MSC-derived exosomes have an immunomodulatory effect due to the interaction of exosomal miRNAs. MSC-derived exosomes are able to transform macrophages from the M0 and M1 phenotypes to the M2 phenotype. Also, they increase secretion of M2-related cytokines such as TGF-β and IL-10 and also decrease M1-related cytokine levels (IL-6, IL-12, and TNF-α)