Two factor-based reprogramming of rodent and human fibroblasts into Schwann cells

Abstract

Schwann cells (SCs) generate the myelin wrapping of peripheral nerve axons and are promising candidates for cell therapy. However, to date a renewable source of SCs is lacking. In this study, we show the conversion of skin fibroblasts into induced Schwann cells (iSCs) by driving the expression of two transcription factors, Sox10 and Egr2. iSCs resembled primary SCs in global gene expression profiling and PNS identity. In vitro, iSCs wrapped axons generating compact myelin sheaths with regular nodal structures. Conversely, iSCs from Twitcher mice showed a severe loss in their myelinogenic potential, demonstrating that iSCs can be an attractive system for in vitro modelling of PNS diseases. The same two factors were sufficient to convert human fibroblasts into iSCs as defined by distinctive molecular and functional traits. Generating iSCs through direct conversion of somatic cells offers opportunities for in vitro disease modelling and regenerative therapies.

Zika Virus Replication in Dorsal Root Ganglia Explants from Interferon Receptor1 Knockout Mice Causes Myelin Degeneration

“…ZIKV can potentially reach the PNS through skin lesions and there are compelling evidences that the virus can cause peripheral nerve damage 18 . Despite the recent technology based on the re-programming of pluripotent stem cells to generate large quantities of human PNS cells 18 , 29 , to date there is no reliable protocol for the in vitro myelination of human induced Schwann cells (hiSCs) and neurons. Therefore, ex vivo myelination models have to be obtained from rodent DRG cultures 30 .…”

Schwann Cell Cultures: Biology, Technology and Therapeutics

“…Ultimately, most methods rely on treatment with neuregulin, alone or together with a cAMP-inducing agents, to drive differentiation along the SC lineage. Regarding genetic approaches, it has been shown recently that the enforced expression of two transcription factors with SC specificity (Erg2/Krox20 and Sox10) suffices to convert human and rodent skin fibroblasts into SC-like cells with capacity to wrap axons and generate compact myelin [65].…”

“…The expression of transcripts encoding for neurotrophins such as NGF, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) has also been confirmed [59] along with the expression of S100β and Egr2. In recent years, researchers have taken advantage of high resolution omics approaches such as RNAseq to identify iSCs from normal and diseased patients [65]. In addition, they have used myelination and neurite outgrowth assays, and transplantation of iSCs in CNS or PNS lesions, to assess their properties in vitro and in vivo, respectively.…”

Transcription Factor-Based Fate Specification and Forward Programming for Neural Regeneration

“…For instance, direct cell fate conversion of rodent fibroblasts into OPCs was achieved by combined overexpression of the TFs Sox10 and Olig2 with either Nkx6.2 (Najm et al, 2013;Matjusaitis et al, 2019) or Zfp536 (Yang et al, 2013). Similarly, myelination-competent Schwann cells can be derived from mouse and human fibroblasts via the combined overexpression of Sox10 and Krox20 (Mazzara et al, 2017;Sowa et al, 2017) and have been shown to accelerate nerve regeneration and motor recovery after transplantation into mice with sciatic nerve transection (Sowa et al, 2017).…”