Peripheral Nerve Reconstruction Therapy Based on Engineered Schwann Cells

The peripheral nervous system (PNS) retains a stronger regenerative potential than the central nervous system (CNS), and even severe injuries can be repaired with certain interventions. The strong regenerative capacity of the PNS is manifested by the ability of damaged peripheral axons to regenerate and re-innervate their targets, a process that is underpinned by the plasticity of Schwann cells (SCs) in the PNS.

Fig. 1 Overview of the repair process of SCs after PNI.¹

SCs are the most important glial cells in peripheral nerves, which facilitate the rapid conduction of electrical impulses by forming myelin sheaths. Following Peripheral Nerve Injury (PNI), chervon cells are essential for nerve regeneration. They partially dedifferentiate into a repair phenotype after injury, and reinitiate the re-expression of developmental genes that support nerve repair. However, not all Schwann cells have a reparative phenotype, which means that they have the ability to promote the removal of axonal debris or myelin debris and maintain axonal regeneration and self-proliferation. In long-distance PNI, the self-repair ability of SCs is limited due to the harsh post-injury microenvironment.

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Creative Biolabs provides an overview of the key molecular regulatory networks of SCs in PNI therapy in recent years to understand the key targets. The table below shows the related services we provide.

Developmental Profiles and Post-Injury Gene Regulatory Networks in Schwann Cells

SCs originate from neural crest cells (NCCs) and pass through two intermediate stages, Schwann cell precursors (SCPs) and immature SCs, before eventually forming myelin sheaths that provide trophic support for axonal growth in peripheral nerves. Normal SCs form myelin sheaths around axons with the following four phenotypes:

• Subtype 1 expresses LOC100134871 and Hbb
• Subtype 2 expresses Cldn19 and Emid1
• Subtype 3 expresses Timp3 and Col5a3
• Subtype 4 expresses Cenpf and Mki67

After PNI, SCs were converted to a homogeneous phenotype and participated in cell proliferation and phagocytosis. After PNI, mature SCs are able to reprogram to a dedifferentiated state through a series of signaling pathways, migrate to the injured area, promote remyelination of damaged nerves, and have a certain role in guiding axonal regeneration. Numerous studies have shown that signaling pathways such as TGF-β1, Slit-Robo, ErbB2 receptor, Hippo, Notch, and so on, are associated with the occurrence of SCs migration process after the occurrence of peripheral nerve injury.

For SCs related research, we also offer a range of research tools, including but not limited to the following:

Targeted Genetically Engineered Schwann Cells

Based on the mechanism of repairing peripheral nerve injury by SCs, key genes in SCs can be up or down-regulated by means of genetic engineering to precisely produce natural products required for repairing peripheral nerve injury. Genetic modification of SCs can be accomplished by different technological means that introduce specific genes or sequences into the genome, including viral vectors, non-viral transfection systems, and CRISPR/Cas9 gene editing techniques.

Existing gene-modified SCs mainly achieve PNI repair through the following signaling pathways.

• Intervention of histone deacetylase (HDAC) affects maturation and myelin formation of SCs through Notch-Hey2 signaling.
• MAPK and Hippo signaling pathways promote the proliferation and myelin regeneration of SCs.
• C-Jun activation and neurotrophic factor overexpression regulate nerve regeneration potential.

Schwann Cells in Association with Biomaterials

Various biomaterials have been used for the treatment of PNI. These biomaterials can mimic the microenvironment through matrix composition, trophic factors, cell adhesion sites, matrix stiffness, topographical cues, and gradients to provide favorable regenerative conditions for peripheral nerve regeneration.

A wide range of biomaterials have been used for peripheral nerve injury repair, which can be broadly categorized into natural and synthetic biomaterials, both of which have distinct advantages and disadvantages. PNI repair techniques have expanded from simple nerve conduit grafts to complex tissue engineering bionics. Engineered peripheral nerve tissues with combined SCs and biomaterials better mimic the cellular composition, extracellular matrix microenvironment, and three-dimensional spatial structure of peripheral nerves, and become the closest grafts to autologous nerves, with a broad market application prospect.

Schwann-like Cells Repair PNI

SCs play an important role in peripheral nerve injury repair, but difficulties in cell acquisition and its expansion limit its use. Meanwhile, SCs are often contaminated by rapidly proliferating fibroblasts during culture, and further isolation, culture and purification are challenging. To overcome these difficulties, scientists have tried to find safer, more reliable and more effective ways to reprogram cells from different sources into induced Schwann-like cells (iSCs).

The origin of human SCs greatly limits their use in the clinic, and the introduction of the concept of iSCs provides a good solution to this problem. However, in the process of constructing iSCs, how to make as many iSCs as possible to present more properties of SCs and fewer properties of other cells is the key problem to be solved.

Along with the continuous innovation of tissue engineering, genetic engineering and stem cell reprogramming, the mission of SCs has gradually developed from simple transplantation therapy to multi-functional composite engineered organoid therapeutic development, which brings a brand-new perspective to the treatment of peripheral nerve injury and its organoid construction.

Reference

1. Su, Qisong, et al. "Engineered Schwann cell-based therapies for injury peripheral nerve reconstruction." Frontiers in Cellular Neuroscience 16 (2022): 865266, used under [CC BY 4.0]

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