Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth

Abstract

Functional recovery after peripheral nerve damage is dependent on the reprogramming of differentiated Schwann cells (dSCs) into repair Schwann cells (rSCs), which promotes axonal regeneration and tissue homeostasis. Transition into a repair phenotype requires expression of c-Jun and Sox2, which transcriptionally mediates inhibition of the dSC program of myelination and activates a non-cellautonomous repair program, characterized by the secretion of neuronal survival and regenerative molecules, formation of a cellular scaffold to guide regenerating axons and activation of an innate immune response. Moreover, rSCs release exosomes that are internalized by peripheral neurons, promoting axonal regeneration. Here, we demonstrate that reprogramming of Schwann cells (SCs) is accompanied by a shift in the capacity of their secreted exosomes to promote neurite growth, which is dependent on the expression of c-Jun (also known as Jun) and Sox2 by rSCs. Furthermore, increased expression of miRNA-21 is responsible for the pro-regenerative capacity of rSC exosomes, which is associated with PTEN downregulation and PI3-kinase activation in neurons. We propose that modification of exosomal cargo constitutes another important feature of the repair program of SCs, contributing to axonal regeneration and functional recovery after nerve injury.

Improvement of sensory neuron growth and survival via negatively regulating PTEN by miR-21-5p-contained small extracellular vesicles from skin precursor-derived Schwann cells

“…In normal situation, the growth of DRGs and sensory neurons was enhanced by SKP-SC-EVs; additionally, after SKP-SC-EV treatment, OGDinjured neurons recovered the expression of functional protein GAP-43, neurite outgrowth, and cell viability. In agreement with this, EVs from SCs or other Schwann- [24,37,38]; moreover, Wang et al provided evidence that SC-exosomes have a therapeutic effect on diabetic peripheral neuropathy in mice and suggested that SC-exosomes' modulation of miRs contributes to this therapy [39]; especially, SCs reprogramming into repair cells can increase miR-21 expression in exosomes, promoting axonal growth [40]. In the same way, SC-like differentiated adipose stem cells could promote neurite outgrowth via secreted exosomes and RNA transfer [41].…”

“…In agreement with this, EVs from SCs or other Schwann-like cells have been evidenced as messenger for cell-to-cell communication, involved in neurite growth and regeneration process. SC-derived exosomes can mediate neuron-glia communication and enhance axonal regeneration through inducing the neuronal growth cone formation [ 24 , 37 , 38 ]; moreover, Wang et al provided evidence that SC-exosomes have a therapeutic effect on diabetic peripheral neuropathy in mice and suggested that SC-exosomes’ modulation of miRs contributes to this therapy [ 39 ]; especially, SCs reprogramming into repair cells can increase miR-21 expression in exosomes, promoting axonal growth [ 40 ]. In the same way, SC-like differentiated adipose stem cells could promote neurite outgrowth via secreted exosomes and RNA transfer [ 41 ].…”

“…As it was reported previously, PTEN gene is one of the main negative regulators of PI3K/Akt pathway, and inhibition of PTEN can facilitate intrinsic regenerative outgrowth of adult peripheral axons [42]; from well-documented papers, we screened out several miRs that implicated with PTEN downregulation and neuronal repair. The literature on EVs suggested that miR candidates, such as miR-19b [43], miR-21 [40], miR-29b-3p [44], miR-233 [45], and miR-304-5p [46], would enable the activation of PI3K and downstream signaling molecules.…”

Modulation of Small RNA Signatures in Schwann-Cell-Derived Extracellular Vesicles by the p75 Neurotrophin Receptor and Sortilin

“…The regulation of neuronal form and function by SCs has been found to be mediated by different forms of intercellular communication, including coupling via local currents in the periaxonal space, paracrine signaling (e.g., ATP, glutamate) and physical coupling via adhesion molecules and gap junctions [7]. In addition to these classic mechanisms, recent findings suggest the occurrence of lateral molecular cargo transfer mediated by secreted extracellular vesicles (EVs) from SCs to axons [8][9][10]. EVs constitute mainly two types of vesicles: exosomes and microvesicles, which are generated by all cell types and derive from multivesicular bodies or through bubbling of the plasma membrane, respectively [11].…”

Schwann Cell Cultures: Biology, Technology and Therapeutics

“…It was found recently that cultured SCs release particulate products in the form of extracellular vesicles or exosomes that are internalized by neurons. SC exosomes are stage-specific and promote axon regeneration in culture and after sciatic nerve injury [119].…”