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Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

ABSTRACT: Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration.

SUBMITTER: Sullivan R

PROVIDER: S-EPMC5187901 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

Sullivan Robert R Dailey Travis T Duncan Kelsey K Abel Naomi N Borlongan Cesario V CV

International journal of molecular sciences 20161214 12

Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve trans ...[more]

PMID: 27983642

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Project description:The rapid and dynamic transcriptional changes of Schwann cells in response to injury are critical to peripheral nerve repair, yet the epigenomic reprograming that leads to the induction of injury-activated genes has not been characterized. Polycomb Repressive Complex 2 (PRC2) catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3), which produces a transcriptionally repressive chromatin environment. We find that many promoters and/or gene bodies of injury-activated genes of mature rat nerves are occupied with H3K27me3. In contrast, the majority of distal enhancers that gain H3K27 acetylation after injury are not repressed by H3K27 methylation before injury, which is normally observed in developmentally poised enhancers. Injury induces demethylation of H3K27 in many genes, such as Sonic hedgehog (Shh), which is silenced throughout Schwann cell development before injury. In addition, experiments using a Schwann cell-specific mouse knock-out of the Eed subunit of PRC2 indicate that demethylation is a rate-limiting step in the activation of such genes. We also show that some transcription start sites of H3K27me3-repressed injury genes of uninjured nerves are bound with a mark of active promoters H3K4me3, for example, Shh and Gdnf, and the reduction of H3K27me3 results in increased trimethylation of H3K4. Our findings identify reversal of polycomb repression as a key step in gene activation after injury.Peripheral nerve regeneration after injury is dependent upon implementation of a novel genetic program in Schwann cells that supports axonal survival and regeneration. Identifying means to enhance Schwann cell reprogramming after nerve injury could be used to foster effective remyelination in the treatment of demyelinating disorders and in identifying pathways involved in regenerative process of myelination. Although recent progress has identified transcriptional determinants of successful reprogramming of the Schwann cell transcriptome after nerve injury, our results have highlighted a novel epigenomic pathway in which reversal of the Polycomb pathway of repressive histone methylation is required for activation of a significant number of injury-induced genes.

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Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

Publications

Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

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