Neurotrophic factors are a heterogeneous group of signaling molecules that play a pivotal role in PNS development, maintenance, and plasticity. The group comprises three multigene families—the neurotrophins (NGF, BDNF, NT-3, and NT-4/5), neuropoetic cytokines (IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), CNTF), and the glial cell line-derived neurotrophic factor ligands (GDNF, neurturin, artemin, and persephin)
[9].
Previous studies have shown that growth factors and cytokines are intricately involved in the axon regeneration, formation of Büngner bands, and neuronal survival
[10]. When sensory and motor neurons are injured, several growth neurotrophic factors and cytokines are up-regulated or activated in neurons and the surrounding tissues. The change in the expression pattern largely relies on the specific type of the damaged neurons. In particular, it has been revealed that NGF and BDNF expression is up-regulated in sensory neurons
[11] and NT-3 in motoneurons
[12], while GDNF exert a pronounced trophic effect on sensory neurons
[13]. Along with that, the expression of TrkA and TrkB, which are high-affinity receptors for neurotrophins NGF, BDNF, and NT-4, correspondingly, is elevated on the growth cone of the regenerating axons
[14]. BDNF and GDNF expression has been reported to be also augmented in Schwann cells. Interestingly, while Schwann cells do not express high-affinity receptors, they do express a low-affinity receptor p75—a common receptor for all neurotrophins (NGF, BDNF, NT3, NT4)
[10].
4. The Role of Exosomes in Regeneration of Peripheral Nerves
Recent advances in cell and molecular biology highlighted a novel mechanism that ensures intercellular communication via exosomes known to be secreted by all cell types
[15][16]. As of today, a large body of evidence indicates that exosomes play a pivotal role in transferring information via their highly selective cargo. Exosomes comprising regulatory and signaling molecules can be released from the source cells of one type and fuse with the target cells of another type, therefore assisting in the integrated intercellular transfer of information
[17]. The content of cargo molecules in exosomes is critically dependent upon their cell origin and physiological or pathological conditions at the moment of exosome formation. Cargo molecules are packed during exosome biogenesis and comprise proteins such as tetraspanins (CD9, CD63, CD81, and CD82), Alix, tumor susceptibility gene 101 (TSG101), Rab GTPases, heat shock proteins (Hsp70, Hsp90), cell adhesion molecules, cytoskeleton proteins, cytokines, regulatory proteins, transcription factors; lipids and genetic cargoes including DNA, mRNA, microRNA, ribosomal RNA (rRNA), circular RNA, long noncoding RNA (lnRNA) (
Figure 1)
[18][19].
Figure 1. The exosome contribution to nerve regeneration. Exosomes are generated from late endosomes, which are formed by inward budding of the limited multivesicular body (MVB) membrane. The MVBs can either fuse with lysosomes for degradation or with the plasma membrane, therefore releasing exosomes into the extracellular space. Released exosomes taken up by damaged neurons and Schwann cells can either enhance or impair PNS.
5. The Role of miRNAs in the Regeneration of Peripheral Nerves
MicroRNAs (miRNAs) are short (~22 bp) single-stranded noncoding RNAs which function by a partial binding (partial complementarity) to mRNA. MiRNAs are currently considered to be “master regulators” of gene expression that orchestrate protein expression at the posttranscriptional level by binding to the 3′UTR of target messenger RNA, either hindering mRNA translation or inducing mRNA degradation. For almost 30 years since miRNAs were discovered, they have received widespread attention due to their potential role in a wide variety of physiological and pathological processes, including neurogenesis, neuronal maturation, embryogenesis, and regeneration of the nervous system among other complicated biological processes. MiRNAs can affect the phenotype of both the recipient and donor cells
[20][21].
6. The Role of Exosomes Derived from Mesenchymal Stem Cells (MSCs) in Peripheral Nerve Regeneration
MSCs are self-renewing multipotent progenitors that can be found in various tissues and organs: bone marrow, adipose tissue, dental pulp, umbilical cord blood, etc. An extensive body of literature indicates that MSCs of different origin have the capacity to promote tissue repair and neuroprotection in vivo and in vitro. Specifically, MSCs promote axonal growth, maintain neuronal survival, and significantly improve functional nerve recovery after injury
[22][23][24].