New research reveals that Schwann cells are capable of spreading myelin across multiple axons


Scientists have discovered that a special type of cell is much more prolific in generating a protective sheath covering nerve fibers than previously believed.

The revelation about Schwann cells raises the possibility of new avenues to treat nerve injuries and various forms of neuropathy.

Further research could prove useful in promoting myelin repair in central nervous system disorders such as multiple sclerosis, where damage to myelin slows or blocks electric signals from the brain.

“This totally overturns the textbook definition of the way Schwann cells work,” said senior author Kelly Monk, Ph.D., professor and co-director of the Vollum Institute at Oregon Health & Science University.

The research published today in the journal Nature Communications.

Two types of cells in the body produce myelin: oligodendrocytes in the brain and spinal cord, and Schwann cells in the rest of the body.

Until now, scientists thought that only oligodendrocytes generated multiple myelin sheaths around axons, the slender projection of a nerve cell that carries electrical signals between cells.

The new research reveals that Schwann cells also are capable of spreading myelin across multiple axons.

Researchers made the discovery after conducting a genetic screen in zebrafish in the Monk laboratory.

They discovered some fish had more myelin than expected, and those fish carried a mutation in a gene called fbxw7.

When they knocked out the gene in genetically modified mice, they discovered an unexpected characteristic: individual Schwann cells began spreading myelin across many axons.

“It highlights a very plastic potential for these cells,” Monk said.

In discovering how Schwann cells generate myelin at the molecular level, the discovery may lead to new gene-therapy techniques to repair damaged myelin in peripheral nervous system disorders such as Charcot-Marie-Tooth disease, a painful inherited form of neuropathy that affects 1 in 2,500 people in the United States.

Both Schwann cells and oligodendrocytes arose at the same point in evolutionary history, with the appearance of jaws in the vertebrate lineage.

Invertebrates lack myelin, and some, like the modern squid, uses thick axons to quickly transmit signals between neurons.

“We could have evolved that way, but our spinal cord would be the diameter of a giant sequoia tree,” Monk said.

Instead, vertebrate axons evolved myelin to protect axons and speed up signal transmission.

To create myelin, Schwann cells evolved to produce it around a single axon in the peripheral nervous system.

Oligodendrocytes, in turn, generated myelin along multiple axons within the more confined environment of the brain and spine—the central nervous system.

“The real estate is fundamentally different in the central nervous system than in the peripheral nervous system,” Monk said.

Monk theorizes that Schwann cells evolved a mechanism to repair damaged myelin on a cell by cell basis, since it would have been common for injuries to occur without necessarily killing the entire organism.

Those traits would have been passed down and strengthened through generations of evolution.

By contrast, remyelination in the central nervous system tended to be an evolutionary dead end since few would have survived a severe whack to the brain or spine.

“There’s no selective pressure in repairing myelin damage in the central nervous system, because you’re probably going to die,” Monk said.

However, the discovery published today suggests a new opportunity to heal the brain and spine.

“Targeting the fbxw7 gene – or downstream pathway molecules – could be a powerful way to promote myelin repair in the central nervous system,” Monk said.

Schwann cell precursors (SCPs) are multipotent embryonic progenitors covering all developing peripheral nerves.

These nerves grow and navigate with unprecedented precision, delivering SCP progenitors to almost all locations in the embryonic body. Within specific developing tissues, SCPs detach from nerves and generate neuroendocrine cells, autonomic neurons, mature Schwann cells, melanocytes and other cell types.

These properties of SCPs evoke resemblances between them and their parental population, namely, neural crest cells.

Neural crest cells are incredibly multipotent migratory cells that revolutionized the course of evolution in the lineage of early chordate animals.

Given this similarity and recent data, it is possible to hypothesize that proto-neural crest cells are similar to SCPs spreading along the nerves.

Here, we review the multipotency of SCPs, the signals that govern them, their potential therapeutic value, SCP’s embryonic origin and their evolutionary connections.

Therapeutic perspectives and importance of peripheral glia plasticity for human health
A number of neurocutaneous diseases likely involve Schwann cells and their progenitors, exploiting their plasticity in a manner similar to the neural crest, including neurofibromatosis type I, leprosy, melanomas, and pigmentation abnormalities, such as nevus of Ota and the so-called “Mongolian spot” (Fig. 3).

Moreover, recent findings suggested that cancers, such as neuroblastoma and pheochromocytoma, may originate from nerve-associated progenitors during development or in adulthood.

Fig. 3
Fig. 3. Human pathologies associated or likely associated with abnormalities of peripheral glial lineage involving melanocyte-related (i.e., nevi, melanomas, and nevus of Ota) or sympathoadrenal-related (i.e., paraganglioma, pheochromocytoma, and neuroblastoma) cases or stemming directly from the glial cells compartment (i.e., neurofibromatosis, Schwannomas, peripheral neuropathies, and leprosy).

Schwannomas are mostly benign tumors growing on the surface of cranial and other peripheral nerves. Although Schwannomas can appear on virtually any nerve, approximately half of cases occur in the head and neck region (Biswas et al., 2007).

In humans, the most common variant is represented by the vestibular Schwannoma affecting the vestibulocochlear nerve (the 8th cranial nerve) and causing hearing problems (Lanser et al., 1992).

Schwannomas are very common in patients with neurofibromatosis, particularly types I and II, given that these tumors are generally composed of Schwann cell derivatives. At the same time, type I neurofibromas (NF) are heterogeneous in composition and may contain fibroblasts, mast cells, perineural cells and melanocytes.

Neurofibromatosis type 1 is a multisystem genetic disorder caused by a mutation in the Neurofibromatosis-Related Protein NF-1 (Nf1) gene. Mutations in the Nf1 gene can inflict a wide range of defects in neural crest-derived tissues (Cichowski and Jacks, 2001) and predispose patients to a variety of cancer types.

Neurofibromas, which are typically benign tumors, are classified as dermal or plexiform. The dermal variant typically manifests around adolescence as hyper-pigmented patches on the skin (café-au-lait macules), which increase in number with age.

Plexiform NFs occur in 20–40% of patients. Unlike dermal NF, which is superficial and benign, plexiform NFs form along peripheral nerves and preferentially affect the para-spinal area associated with the dorsal root ganglia (DRG).

These plexiform masses can grow to large tumors and become malignant.

The initiation of such tumors has remained elusive; however, the origin cell clearly belongs to the peripheral glial lineage.

Recently, an elegant and detailed mouse study addressed the known embryonic Schwann cell subgroups and demonstrated that PLP1+/GAP43+ cells are the main source of NF tumors (Chen et al., 2014). Consistently, the deletion of murine transcription factor Runx1 from SCPs delays NF formation in vivo (Li et al., 2016).

Approximately all NF patients display pigmented patches on the skin called café-au-lait macules together with the presence of abundant melanocytes within actual tumors.

These features are indicative of a strong association among Schwann cell progenitors, melanocytes and cancers derived from these cell types. Consistent with this notion, Cre-mediated deletion of the Nf1 gene specifically in peripheral glial progenitors (after neural crest cells completed their migration and differentiation) leads to the formation of NF tumors associated with pigmentation (Wu et al., 2008), as extensively reviewed in (Adameyko and Lallemend, 2010).

Further proof of the association between SCPs and melanocytes includes the fact that nevi and melanoma cancer cells express Schwann cell markers in mice and humans (Aso et al., 1988, Iwamoto et al., 2001, Warner et al., 1981). Conversely, melanotic schwannomas, a group of tumors originating presumably from Schwann cells, express melanocyte markers (Er et al., 2007).

Nevi, or pigmented moles, are localized benign skin lesions appearing after birth and affecting almost everyone.

However, some nevi can become a melanoma, a malignant cancer of the skin with an increased incidence worldwide (Erdmann et al., 2013). Melanocytes were considered to be immediate derivatives of migratory neural crest cells (Kawakami and Fisher, 2011, Sommer, 2011) until it was demonstrated that they can originate from SCPs associated with the growing nerves (Adameyko et al., 2009). In mouse, abnormalities in this mechanism might be responsible for conditions, such as extracutaneous melanomas (and some other melanoma subtypes), the nevus of Ota and the so-called “Mongolian disorder”.

The nevus of Ota is a disorder where melanocytes form massive blue/gray patches that are deposited along the first and second branches of the cranial trigeminal nerve, demonstrating a clear connection with neuroanatomy. Although primarily affecting the skin, extracutaneous spreading to the eye sclera is frequent (Radhadevi et al., 2013) (Fig. 3). A similar condition is the so-called “Mongolian spot”, which is characterized by the appearance of blue/gray spots predominantly in the lumbosacral area at birth. Although these spots disappear relatively soon after birth in most cases, metabolic abnormalities have been reported in affected people (Gupta and Thappa, 2013). In light of this notion, a better understanding of the developmental dynamics is necessary for the clear identification of the origin cell for such pathologies, thereby providing new potential targets.

Recently, new data demonstrated that chromaffin cells of the adrenal medulla are derived from SCPs during murine embryo development via a newly identified progenitor cell expressing markers of both glial and chromaffin (sympathoadrenal) lineages and thus named “bridge” cell (Furlan et al., 2017).

The sympathoadrenal lineage is the source of neuroblastoma, the most common extracranial solid tumor of early childhood (Maris et al., 2007), and pheochromocytoma, which originates from rather mature chromaffin cells mostly during adult life (Turchini et al., 2018).

Consistent with this notion, neuroblastoma is thought to form from proliferating sympathetic nervous system precursors during development, whereas pheochromocytomas are considered to stem from mature chromaffin cells after embryonic development is completed (due to their late onset despite the existence of rare pediatric subtypes). In humans, neuroblastomas and pheochromocytomas are clinically heterogeneous (Burnichon et al., 2016, Chicard et al., 2017).

The factors that define such a spectrum of tumor subtypes and their variable behaviors are unclear; however, some important differences can result from the properties of a cell of origin.

Chromaffin cells have long been considered to be a product of common sympathoadrenal precursor cells subsequently derived from neural crest stem cells migrating dorso-ventrally towards the dorsal aorta.

According to this notion, this common precursor pool later splits and generates the sympathetic lineage and the chromaffin precursors in a rather ventral position in mouse and chick (Huber et al., 2009, Saito et al., 2012). Rather unexpectedly, a number of experiments, including lineage tracing and single-cell sequencing of SCPs, bridge and chromaffin cells, revealed a progressive transition between cell types.

In-depth molecular and bioinformatics analysis revealed that after an initial step where SCPs proliferate to expand their pool, they transiently halt cell division and become immature chromaffin cells via a “bridge” step before resuming proliferation and expanding the pool of chromaffin cells (Furlan et al., 2017).

This proliferation halt is similar to that described for sympathetic neurons (Gonsalvez et al., 2013). Expression of Mycn, the amplification of which correlates with progression and prognosis of neuroblastoma, was detected in both SCP and bridge cells (Furlan et al., 2017).

Thus, the diversity and hierarchy of these new chromaffin progenitor cells may underlie some specific properties of particular subtypes of neuroblastoma and pediatric pheochromocytoma. Future work should address the potential of these glial and bridge nerve-associated progenitors in the generation of various tumors.

The plasticity of adult and embryonic peripheral glial cells is beneficial to our body during the nerve damage by transforming Schwann cells into reparative cell types (Boerboom et al., 2017, Han et al., 2017).

Consistent with this notion, growing evidence suggests that Schwann cells give rise to specialized cells that inhabit skin wounds and promote the wound closure and healing via a paracrine modulation (Johnston et al., 2013, Parfejevs et al., 2018).

Such regenerative plasticity of the Schwann cell lineage can be harnessed as an advantage by pathogens.

In humans, an example of this phenomenon involves Mycobacterium leprae infection of Schwann cells, resulting in a condition known as leprosy or Hansen’s disease. Recently, extensive research performed in mouse models revealed that M. leprae highjacks the molecular program of mature Schwann cells and reverts them to the stem-like mesenchymal state by turning off adulthood Schwann genes and turning on the mesodermal-like developmental program (Masaki et al., 2013).

Such de-differentiated Schwann cells can proliferate, form granulomas (skin bumps) and even migrate along the nerves to other body locations.

Indeed, the fact that mature Schwann cells can be reprogrammed and reverted to a specific progenitor state by a bacterium is surely striking.

However, in the case of Hansen’s disease, the re-derived progenitors form only highly contagious aberrant masses of tissue (Fig. 3).

What would occur if we could de-differentiate adult Schwann cells and then re-direct them into the formation of new desirable cell types for regenerative purposes?

Schwann cells are found everywhere in the body along the nerves, functioning as a generous and almost omnipresent cell source that can be instructed and reprogrammed in vivo.

On the other hand, devising strategies to culture and expand these cells in vitro for the purpose of transplantation is of crucial importance.

Schwann cells and their progenitors can be obtained in large numbers from induced pluripotent stem cells (IPSCs) (Kim et al., 2017, Ma et al., 2015). Unlike embryonic stem cells (ESCs), ISPCs can be derived from a patient’s own somatic cells (autologous), differentiated into SCPs and transplanted back into patients.

In vitro, newly derived SCPs become mature functional Schwann cells, secreting neutrophins and myelinating rat axons. When transplanted in vivo, human pluripotent stem cells (hPSCs) facilitate axonal regeneration (Kim et al., 2017).

Additionally, avian (quail) Schwann cells and their progenitors expanded in vitro can generate other cell types, including myofibroblasts (Real et al., 2005) or melanocytes (Dupin et al., 2003), in a dish.

Taken together, many recent studies described remarkable steps forward in understanding SCPs and Schwann cells in health and disease (summarized in Fig. 3).

In particular, SCPs are now considered to be a potential source of other cell types in addition to mature Schwann cells.

The advent of the single cell transcriptomics era considerably improved our ability to gather data about molecular changes during development or regeneration and enabled an unprecedented degree of exploration.

In particular, the identification of a new nerve-associated cell, the so-called “bridge” progenitor between SCPs and mature chromaffin cells, forces the community to reconsider what we previously thought about the normal development of sympathoadrenal tissues and corresponding developmental abnormalities leading to the onset of life-threatening conditions, such as neuroblastoma and pheochromocytoma.

If one of our main goals is to cure neural crest-derived cancers and other diseases stemming from Schwann cells or their progenitors, a multidisciplinary approach must be involved.

More information: Breanne L. Harty et al, Myelinating Schwann cells ensheath multiple axons in the absence of E3 ligase component Fbxw7, Nature Communications (2019). DOI: 10.1038/s41467-019-10881-y

Journal information: Nature Communications
Provided by Oregon Health & Science University


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