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Direct Conversion to Achieve Glial Cell Fates: Oligodendrocytes and Schwann Cells
International Journal of Stem Cells 2022;15:14-25
Published online February 28, 2022;  
© 2022 Korean Society for Stem Cell Research.

Wonjin Yun1,2, Yong Jun Kim3,4, Gabsang Lee1,2,5

1Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Korea
4Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
5The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Correspondence to: Gabsang Lee
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
E-mail: glee48@jhmi.edu
Received January 14, 2022; Accepted February 3, 2022.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Glia have been known for its pivotal roles in physiological and pathological conditions in the nervous system. To study glial biology, multiple approaches have been applied to utilize glial cells for research, including stem cell-based technologies. Human glial cells differentiated from pluripotent stem cells are now available, allowing us to study the structural and functional roles of glia in the nervous system, although the efficiency is still low. Direct conversion is an advanced strategy governing fate conversion of diverse cell types directly into the desired lineage. This novel strategy stands as a promising approach for preliminary research and regenerative medicine. Direct conversion employs genetic and environmental cues to change cell fate to that with the required functional cell properties while retaining maturity-related molecular features. As an alternative method, it is now possible to obtain a variety of mature cell populations that could not be obtained using conventional differentiation methods. This review summarizes current achievements in obtaining glia, particularly oligodendrocytes and Schwann cells.
Keywords : Direct conversion, Differentiation, Oligodendrocyte, Schwann cell, Disease modeling
Introduction

Glial cells, including astrocytes, oligodendrocytes, Schwann cells, ependymal cells, and microglia, are non-neuronal cells in the nervous system, which are more abundant than neurons (1). They support the morphological and functional features of neurons, and maintain the homeostasis in the nervous system (2). The abnormal activation of astrocytes, which are the most abundant cell type in the central nervous system (CNS), has been regarded as a cellular feature of pathological conditions (3). Likewise, oligodendrocytes and Schwann cells are also thought to be involved in the pathogenesis of several neurological diseases (4). Since deriving glial cells from individual patients is extremely difficult, it is now believed that obtaining glial cells from human pluripotent stem cells (hPSCs) is more feasible and efficient (5-7). However, as glial cells, particularly oligodendrocytes and Schwann cells, naturally develop during the late stage of nervous development through neurogenesis-to-gliogenesis switch, these developmental characteristics are considered as obstacles for complete differentiation of glial cells from hPSCs, and even the differentiated glial cells have functionally immature features. While human neuronal development begins at 6∼8 gestational week (8), oligodendrocytes differentiation begins around 18∼20 gestational week (9), and Schwann cells are observed after 7th week (10). Moreover, the myelination process continues until after the postnatal stage (11). Hence, hPSC-derived glial cells have not been adequately applied to study many neurological diseases associated with the impaired functions of these glial types (12).

Advances in stem cell and direct conversion technology have provided invaluable research models that describe the pathophysiology of human neurological diseases (13). In addition to the already mentioned limitations of differentiating glial cells, concerns related to cellular defects, such as the lack of functionalities based on the immature states of differentiated cells, are being raised. Direct conversion, which bypasses the pluripotent stage and irreversibly converts a certain cell type into a desired cell types (14), is one of the innovations in stem cell field. Numerous studies have shown that the cell fate can be switched to neuronal or glial cells by introducing lineage-specific transcription factors that regulate cellular plasticity and lineage flexibility (15, 16). This newly developed methodology is designed to transfer the cellular and molecular maturity of native cells intact to their converted counterparts. Additionally, it is considered as a promising alternative to avoid the biological or technical obstacles of conventional cell fate reprogramming, namely the necessity of reprogramming cells to the pluripotent state or embryonic stage. Cell fate conversion technique has been used in recent studies to improve the understanding of neurological diseases and to propose novel potential therapeutic approaches (17).

In this review, we discuss the recent progress in the utilization of myelinating glial cells, represented by oligodendrocytes and Schwann cells. This article covers both differentiation and direct conversion to obtain these cell types and provides prospects for future directions in light of current interest in the role and importance of glial cells in the nervous system.

Glia in the Nervous System

Glial cells in the CNS include astrocytes, oligodendrocytes, ependymal cells and microglia; whereas glial cells in the peripheral nervous system (PNS) include Schwann and satellite cells (18). These cells are responsible for maintaining the homeostasis and function of the nervous system, which includes providing physical and metabolic support to neurons and insulating neuronal axons (19). In the brain, glial cells exert various roles such as cerebrospinal fluid (CSF) production and distribution, blood-brain barrier regulation, neuro transmitter and ATP uptake and release, and myelin sheath formation depending on the cell type and anatomical location (20). In contrast, in spinal nerves and peripheral nerves, glial cells are known to be involved in efficient transmission of electrical signals and protection of neurons, mainly through the myelination (21).

Recently, in addition to their physiological functions, the role of glial cells in various pathological conditions has been suggested (22). Astrocytes and microglia are known to be related to the activation of inflammatory responses involved in the progression of brain diseases due to ischemic injury, infections, and genetic causes, and their cellular changes are recognized as markers of acute or chronic pathological conditions (23). Another type of glial cells, ependymal cells, form a cellular lining, control CSF production, and prevent CSF leakage (24, 25). Although previous studies have reported the differentiation of ependymal cells into new neurons in various pathological environments, whether they are neural stem cells with self-renewal capacity remains unclear (26-28). While the aforementioned types of glial cells have properties that are attributed to organ-specific features of the brain, oligodendrocytes and Schwann cells have similar functions despite their distinct anatomical location (29). Although Schwann cells include a non-myelinating subpopulation (30), both types of glial cells myelinate neuronal axons. Histological analyses of various neurological diseases have reported demyelination as a pathological hallmark (31); however, it is unclear whether intrinsic factors within glial cells cause demyelination triggering the development of the disease or it is only an intermediate phenotype of disease progre-ssion. Defects of these cells due to genetic factors or unknown pathogenesis cause serious clinical symptoms, and in many cases, immunological response is also involved. Denaturation of the myelin sheath is often observed in various hyper-immunity diseases (32, 33). Additionally, oligodendrocytes and Schwann cells have been reported to be involved in neuroinflammatory mechanisms (34, 35). Therefore, identifying the cellular mechanisms of oligodendrocytes and Schwann cells in pathological environments may contribute to the understanding of a variety of demyelinating diseases.

Differentiation of Glial Cells from Pluripotent Stem Cells

During embryonic development, oligodendrocyte progenitor cells (OPCs) are produced from the motor neuron progenitor domain in the ventral neuroepithelium of the spinal cord and differentiate into oligodendrocytes, whereas Schwann cell precursors (SCPs) originate from neural crest cells migrating along the dorsoventral tract and differentiate into Schwann cells. In this context, protocols for differentiating each cell type have been established to mimic the developmental processes along the developmental lineage (CNS or PNS).

Developmental pathways differ depending on the anatomical location of oligodendrocytes in the nervous system (36), and distinct pathways towards the ventral spinal cord or forebrain fates have been proposed as pathways for the differentiation of oligodendrocytes from hPSCs (Table 1). Differentiation into the ventral spinal cord is mimicked by ventralization and caudalization, which are stimulated by the activation of the retinoic acid and sonic hedgehog signaling pathways that induce the expression of OLIG2 (5, 37-39); forebrain (39, 40) and hindbrain (41) patterning can be achieved by rostralization through inhibition of the Wnt signaling pathway. Most studies on subsequent differentiation have adopted stepwise methods through sphere formation under appropriate culture conditions including platelet-derived growth factor (PDGF), neurotrophin-3, cyclic adenosine monophosphate, and triiodothyronine that promote the development of oligodendrocytes. Using stepwise strategies, Wang et al. (38) reported large-scale production of hPSC-derived OPCs expressing OLIG2, PDGFRa, NKX2.2 and SOX10. Since conventional methods require much time (more than 100 days), subsequent studies have attempted to improve protocols to overcome the long-term period of differentiation (40, 42-45). Recently, Douvaras et al. successfully established a straightforward, rapid, and efficient differentiation method that enables the generation of oligodendrocytes within 70 days (42); however, whether the protocol facilitates the large-scale expansion of clinically compatible progenitor cells remains unknown. Moreover, attempts have been made to reduce the differentiation period using the strong fate commitment role of transcription factors (46-48). SOX10, discovered in the screening of transcription factors involved in the fate decision of OPCs, was sufficient to differentiate neural progenitor cells into oligodendrocytes expressing mature oligodendrocyte markers O4 or myelin basic protein (MBP) rapidly within 3 weeks of its introduction (47, 48). Furthermore, the combined expression of SOX10, OLIG2 and NKX6.2 increased the efficiency of O4-expressing oligodendrocytes to 70% (46). Although the generation of mature oligodendrocytes expressing MBP can be achieved in a relatively short period by the introduction of certain transcription factors, the effect of artificially shortening the differentiation period on the reconstruction of pathophysiological features of differentiated cells is still unknown.

Table 1 . Summary of oligodendrocyte differentiation

SpeciesCell sourcesRegional identityTarget cell type (Efficiency)Duration (Days)Self-renewalIn vitro disease modelingIn vivo transplantationReferences
HumanhESCsSpinal CordPDGFRα OPCs (>80%)>90 days
Not shownNot shownNewborn shiverer miceHu et al., 2009
MBP OLs (Not shown)>120 days
MouseEpiSCsSpinal CordPDGFRα OPCs (∼90%)>10 days>passage 8Not shownNewborn shiverer miceNajm et al., 2011
MBP OLs (Not shown)>13 days
HumanhESCs
hiPSCs
Spinal CordPDGFRα OPCs (>30%)>120 days
Not shownNot shown (Schizophrenia, as shown in Windrem et al., 2017; Huntington’s Disease, as shown in Osipovitch et al., 2019)Newborn shiverer miceWang et al.,
2013
MBP OLs (Not shown)∼200 days
HumanhESCsForebrain
Spinal Cord
NG2 OPCs (∼87%)>120 days
Not shownNot shown (As shown in Djelloul et al., 2015)Not shownStacpoole et al., 2013
MBP OLs (∼5%)>135 days
HumanhESCs
hiPSCs
Spinal CordO4 OPCs (∼70%)>50 daysNot shownNot shown (Pelizaeus-Merzbacher Disease, as shown in Nevin., 2017; Schizophrenias, as shown in McPhie et al., 2018; Alexander disease, as shown in Li et al., 2018)Newborn shiverer miceDouvaras et al., 2014 and 2015
MBP OLs (∼20%)∼75 days
HumanhESCs
hiPSCs
ForebrainPDGFRα OPCs (25%)>50 days
Not shownNot shownIrradiated ratsPiao et al., 2015
MBP OLs (Not shown)>85 days
Monkey
Human
mESCs
hiPSCs
Spinal CordPDGFRα OPCs (>10%)>57 days
Not shownNot shownNewborn C57BL6/J miceYamashita et al., 2017
MBP OLs (∼4%)>73 days
HumanhESCsNot shownPDGFRα OPCs (>90%)>28 daysNot shownNot shownAdult rat spinal cordKim et al., 2017
HumanhESCs
hiPSCs
HindbrainPDGFRα OPCs (>20%)>65 daysNot shownNot shownAdult shiverer miceYun et al., 2019
MBP OLs
(>3%)
∼120 days


Schwann cells originate from multipotent migratory neural crest cells that are specified at the neural plate border region and differentiate into neurons and glia in the PNS. Most of the early developmental studies on neural crest cells and Schwann cells have been primarily conducted in different organisms because of the spatiotemporal properties of neural crest cells during embryonic development (49, 50). Developmental mouse embryos have been sacrificed to study neural crest biology (51, 52) and avian models such as quail and chick that are capable of tracking live neural crest cells also have been commonly used (53). Lee et al. (54, 55), showed that human neural crest cells can be isolated from the periphery of hPSC-derived neural rosettes representing the early developing neuroepithelium and established feeder-free reliable protocols to establish for neural crest lineages, including peripheral neurons and Schwann cells. The differentiation and maturation processes of Schwann cells have not yet been studied in detail. Multiple studies have attempted to differentiate Schwann cells by administrating factors secreted by peripheral neurons, such as PDGF and neuregulin-1, since Schwann cells directly contact with peripheral neuronal axons (56). Subsequent studies developed direct protocols for the differentiation of Schwann cells through the intermediate stage of SOX10- and p75-positive neural crest cells, which required approximately 50 days, depending on the specific protocol (Table 2) (57-62). While GFAP expression is uniquely found in astrocytes not oligodendrocytes in the CNS, differentiated Schwann cells expressed GFAP as well as S100β representing functional overlap of the CNS and PNS glia besides myelination. Most studies have commonly used S100β, GFAP or MPZ as markers for differentiated Schwann cells (63). The regenerative capacity of the resulting cells has been validated and shown to be comparable to that of primary human Schwann cells in peripheral nerve injury models (60, 62, 64). In addition, the method developed by Kim et al. (62) not only enables differentiation into Schwann cells within 32 days but also allows the stable expansion of SCPs for more than 35 passages, providing insight into possible cell-based therapeutic strategies for peripheral nerve injury. Recently, Mukherjee-Clavin et al. (7) obtained a population of pure Schwann cell precursors (SCPs) from neural crest cells that differentiated as a result of natural interactions with peripheral neurons. Furthermore, Schwann cells differentiated from Charcot-Marie-Tooth (CMT) 1A patient-induced pluripotent stem cells (iPSCs) and preimplantation genetic diagnosis-human embryonic stem cells (hESCs) have contributed to reveal the pathological mechanisms of CMT and other diseases, thereby providing a promising research tool for disease modeling. Although the protocol reported in this study is longer (more than 80 days) than that of other studies, it is still considered that the resulting differentiated Schwann cells are insufficient to represent the mature patient’s PNS, as the myelination efficiency in vitro was comparably low, but effective nerve regeneration was achieved when transplanted into animal models.

Table 2 . Summary of Schwann cell differentiation

SpeciesCell
sources
Target cell type
(Efficiency)
Duration
(Days)
In vitro disease modelingIn vivo transplantationReferences
HumanhESCs
hiPSCs
p75 NCSCs (∼30%)>28 days
Not shownChick embryos and adult NOD/SCID miceLee et al., 2007
Lee et al., 2010
GFAP or S100β SCs (>5%)>109 days
HumanhESCsGFAP or S100β SCs (∼60%)∼84 daysNot shownNot shownZiegler et al., 2011
HumanhESCs
hiPSCs
p75 NCSCs (Not shown)>22 days
Not shownAdult rat sciatic nerveWang et al., 2011
GFAP or S100β SCs (Not shown)>34 days
HumanhESCs
hiPSCs
p75 NCSCs (∼46%)>14 days
Not shownIn Ovo NCSC InjectionLiu et al., 2012
GFAP or S100β SCs (Not shown)>54 days
HumanhESCs
hiPSCs
p75 NCSCs (∼80%)>8 days
Not shownNot shownKreitzer et al., 2013
GFAP SCs (Not shown)Not mentioned
HumanhESCs
hiPSCs
SOX10 SCPs (∼99%)>24 days
Not shownC57BL/6 mice sciatic nerve injury modelKim et al., 2017
S100β or MPZ SCs (Not shown)>31 days
HumanhiPSCsp75 NCSCs (Not shown)>20 days
Not shownAdult athymic nude rat sciatic nerveHuang et al., 2017
GFAP or S100β SCs (Not shown)>41 days
HumanhESCs
hiPSCs
PGD−hESCs
CD49d+ SCPs (∼18%)>21 daysCMT1A pathogenesisMouse tibial nerve and rat models of chronic peripheral nerve denervationMukherjee-Clavin et al., 2019
GFAP or S100β+ SCs (Not shown)∼101 days


Both oligodendrocytes and Schwann cells develop continuously at the postnatal stage and are known to require time-consuming differentiation strategies in vitro. Moreover, in all differentiation methods from hPSCs developed to date, cells undergo epigenetic reprogramming. (65, 66). Epigenetic state of the hESCs is immature and thus maintains the euchromatin state in whole chromosome (67). In the process of establishing iPSCs from adult fibroblasts, it is known that OCT4, which regulates epigenetic regulatory mechanisms, reconstructs the mature epigenetic state of fibroblasts similar to that of embryonic stem cells (68). It is known that the initialized epigenetic characteristics change in the direction of limiting cell lineage and increasing cellular maturity as cell differentiation progresses (69). Therefore, the relatively short developmental period compared to that of living organs, the absence of stimuli for cellular aging, and the lack of a clear understanding of epigenetic changes that induce cellular maturation are still obstacles to obtaining biologically reliable cells. Current challenges to obtain functional myelinating cells from hPSCs may hamper studying myelination-related diseases. Despite extensive studies on differentiation, very little is known about the genetic control of the transition from hPSCs to myelination competent cells. Understanding the intrinsic and extrinsic factors including transcription factors governing functional myelinating cells will lead to acquiring authentic oligodendrocytes and Schwann cells.

Direct Conversion as an Alternative to Differentiation

To overcome the limitations arising from stem cell reprogramming and differentiation procedures, recent studies have shown promising results for the direct conversion of fibroblasts into oligodendrocytes (Table 3) and Schwann cells (Table 4).

Table 3 . Summary of oligodendrocyte conversion

SpeciesCell
source
Reprogramming factorsTarget cell type (Efficiency)Duration
(Days)
Self-renewalIn vitro disease modelingIn vivo transplantationReferences
MouseFibroblastsSOX10, OLIG2, NKX6.2PLP1 iOPCs (>20%)>21 days
>passage 5Not shownNewborn shiverer miceNajm et al., 2013
MBP iOLs
(Not shown)
>24 days
MouseFibroblastsSOX10, OLIG2, ZFP536O4 iOPCs (>15%)>21 days
Not shownNot shownNewborn shiverer miceYang et al., 2013
MBP iOLs
(>10%)
>24 days
MouseFibroblastsOCT4A2B5 iOPCs (>90%)>35 days
>passage 31Not shownAdult rat SCI modelsKim et al., 2015
MBP iOLs (Not shown)>63 days
MouseAstrocytesSOX10NG2 iOPCs (>80%)>16 daysNot shownNot shownIn vivo conversion in cuprizone-induced demyelinated miceKhanghahi et al., 2018
MouseAstrocytesSOX2PDGFRα iOPCs (>70%)>14 daysNot shownNot shownIn vivo conversion in cuprizone-induced demyelinated miceFarhangi et al., 2019
MouseFibroblastsChemical condition (M9)A2B5 iOPCs (>60%)
>18 days
>passage 8Not shownNot shownChang Liu et al., 2019
MBP iOLs (Not shown)>28 days
HumanFibroblastsOCT4A2B5 iOPCs (∼10%)>14 days
>passage 10Not shownAdult shiverer mice and EAE-induced modelYun et al., 2022
MBP iOLs (∼3%)>50 days


Table 4 . Summary of Schwann cell conversion

SpeciesCell sourceReprogramming factorsTarget cell type (Efficiency)Duration (Days)In vitro disease modelingIn vivo transplantationReferences
HumanFibroblastsSOX10SOX10 NCSCs (∼2%)>14 days
Not shown (CMT1A pathogenesis, as shown in Mukherjee-Clavin et al., 2019)Chick embryosKim et al., 2014
MPZ or S100β SCs (Not shown)∼35 days
HumanFibroblastsChemical conditionGFAP or S100β SCs (Not shown)>27 daysNot shownNot shownThoma et al., 2014
HumanFibroblastsSOX10, EGR2S100β SCs (∼43%)>10 daysNot shownThe sciatic nerve of nude and NOD/SCID miceSowa et al., 2017
Human (mouse)FibroblastsSOX10, EGR2S100β SCs (>5%)
>14 days
Not shownNot shownMazzara et al., 2017
MPZ SCs (Not available)>21 days
HumanFibroblastsChemical conditionGFAP or S100β SCs (Not shown)>9 daysNot shownThe sciatic nerve injury rat modelKiada et al., 2019
HumanFibroblastsOCT4, SOX2, KLF4, MYCL1, and LIN28 and p53 shRNASOX10 SCPs (∼97%)
>18 days
Not shownThe sciatic nerve injury mouse modelKim et al., 2020
S100β or NGFRSCs (>95%)>25 days


The reporter cell line expressing green fluorescent protein along with PLP1 identified lineage-specific transcription factors for OPCs. Additionally, induced expression of OLIG2, SOX10, and NKX6.2 or ZFP536 which are involved in OPC development, led to rodent fibroblasts developing into induced OPCs (iOPCs) within 3 weeks (70, 71). The obtained cells exhibited typical bipolar morphology and not only expressed various OPC markers including NG2, A2B5, and S100β presenting gene expression profiles consistent with those in bona fide OPCs but also could give rise to mature O4 and MBP-positive oligodendrocytes in vitro and successfully generated myelin structures for neuronal axons when transplanted into hypomyelinated Shiverer mice in vivo. In addition, the combination of SOX10, OLIG2, and NKX6.2 has been reported to provide an enhanced driving force for fate conversion towards OPCs through differentiation (46) and direct conversion (70) demonstrating relatively straightforward set of genes. Previous studies have attempted to minimize the number of transcription factors utilized for direct conversion (72-75). OCT4 has been proposed as a single factor sufficient for converting rodent fibroblasts into proliferative iOPCs, which promote extensive remyelination by retaining locomotor activity that facilitates access to the wound site when transplanted into an animal model of spinal cord injury (72). Similarly, the generation of iOPCs was achieved by introducing a single transcription factor, SOX2 or SOX10, into rodent astrocytes in an in vitro and in vivo manner (73, 74). Weider et al. (76) reported that overexpression of SOX10 drives the cellular properties of peripheral satellite glia to resemble those of oligodendrocytes in vivo. Recent attempts to convert human fibroblasts into iOPCs has been also successful (77). Ectopic expression of OCT4, along with small molecules, directly converts human fibroblasts into expandable iOPCs. These cells exhibit not only in vitro differentiation potential into oligodendrocytes, but also in vivo differentiation potential when transplanted into experimental autoimmune encephalomyelitis mice, providing insight into whether iOPCs can be a useful population for cell-based therapies.

Despite the great efforts aimed to successfully generate human iOPCs, the mechanism of the transcription factors used in the conversion process is still not clearly understood. Yun et al. (77) employed OCT4 as a pioneer factor governing the opening of chromatin regions otherwise generally inaccessible in differentiated cells (78, 79). In line with this, Dehghan et al. (80) reported that the forced expression of OCT4 in combination with the administration of valproic acid to the demyelinated mouse brain enhanced myelin sheath repair, providing evidence for functional link between an OCT4 and the regulation of myelin related factors. However, OCT4 alone-driven methods exhibit low efficiency in converting ratio of SOX10-expressing cells and induce uncharacterized heterogeneous populations (77). By contrast, the combined use of SOX10, OLIG2, and NKX6.2 strongly favored commitment to the specific OPC lineage from hPSCs-derived neural progenitor cells (differentiation) (46) and rodent fibroblasts (direct conversion) (70, 81), suggesting that cell fate conversion to OPCs can be achieved with SOX10-combined methods in a more favorable manner.

In contrast to oligodendrocytes, which express SOX10 only at the beginning of OPC specification after neural tube formation, Schwann cells retain the expression of SOX10 throughout the entire differentiation process ranging from the migrating neural crest stage to becoming fully differentiated myelinating Schwann cells. Kim et al. (16) reported the generation of induced neural crest cells with SOX10 overexpression in combination with small molecules that activated the Wnt signaling pathway, and mature Schwann cells expressing endogenous SOX10 were acquired by a subsequent differentiation process. To obtain a more specific Schwann cell fate, EGR2 and SOX10 were employed to rapidly convert cells into Schwann cells expressing MPZ (82, 83). EGR2 is known to be involved in the myelination process as well as in the initiation of the terminal differentiation of Schwann cells into the MBP- and MPZ-positive mature state (84, 85). Hence, the combination of SOX10 and EGR2 allows rapid and efficient conversion into Schwann cells; however, whether these cells harbor functional myelin-competent capacity, comparable to that of bona fide Schwann cells in vivo, remains elusive. As shown in a recent study by Mukherjee-Clavin et al. (7), Schwann cells derived from SOX10-induced neural crest cells (16) can be effectively applied to model specific diseases, such as CMT1A. Therefore, it may be more promising to identify additional transcription factors involved in Schwann cell development in human systems, such as SOX9, TFAP2A, and PAX3, as shown in rodent oligodendrocyte studies (46, 70), and it would be effective to employ genes used in oligodendrocyte studies to achieve a better efficiency. Indeed, a recent study reported the successful generation of induced SCPs (iSCPs) using pluripotency factors (OCT4, SOX2, KLF4, L-MYC, LIN28, and p53-shRNA) under appropriate culture conditions (86). This is a feasible approach for the application into a clinical setting in terms of large-scale expansion and permitting differentiation into mature Schwann cells while maintaining the identity of iSCPs. However, the introduction of pluripotency factors has raised concerns about the risks of residual expression. In fact, OCT4, SOX2, KLF4, L-MYC, and LIN28 are all known as oncogenes or proto-oncogenes (87-89). In particular, strong expression of OCT4 and SOX2 was confirmed in Schwannoma (90), and LIN28 also contributes to embryonal tumor progression in the CNS (91). Moreover, inhibition of p53, a potent tumor suppressor, further amplifies concerns about tumor development (92). As aforementioned, determining the transcription machinery of the myelination process among the complete pool of candidate genes has been made in oligodendrocytes through direct conversion study, whereas only a few transcription factors involving SCs development have been tested and screened for inducing SCs. Furthermore, converted human iSCs still exhibited incomplete myelination compared to rodent counterpart, suggesting necessity of additional transcription factors screening for functional myelinating SCs.

Perspectives

Transcription factor-mediated direct conversion is accomplished by the reactivation of epigenetically repressed state of target genes and successful reprogramming largely depends on native cell types, whereas the differentiation process differentiates the desired cells by applying the developmentally established procedures from cells in a pluripotent state. Thus, it is difficult to establish a consensus regarding protocol and optimal conditions such as the driving transcription factors and the duration of the protocol. Although direct conversion from cell types of the same lineage can be efficiently conducted, it is considered more feasible to utilize cell sources that are readily accessible. For example, direct conversion of human fibroblasts to OPCs and SCPs has been achieved (7, 16, 77, 86). However, fibroblasts, in particular, are heterogenous and considered to have significant differences in properties depending on the anatomical locations and tissue types from which they are derived (93-95). Therefore, it is necessary to verify the applicability of the protocol in fibroblasts obtained from different parts of the human body and to clarify the molecular mechanisms of the introduced transcription factors and the role of environmental factors regulated by small molecules in more detail. Moreover, direct conversion is recognized as an artificial process that does not follow the natural stages of development and utilizes the strong driving forces of ectopic transcription factors. Accordingly, concerns have been raised regarding the unpredictable risks posed by the use and retention of such transcription factors. However, many studies showed that ectopic expression of transcription factors enable achievement of self-renewal ability in iOPCs and iSCPs transiently that would otherwise be inaccessible through conventional differentiation methods in human (Table 3, 4). The use of transcription factors for establishing expandable cells may facilitate clinical-based studies requiring large numbers of cells and reveal the precise mechanisms for intrinsic cues governing self-renewal ability. Interestingly, chemical- or small molecule-based approaches have been reported to enable the generation of iOPCs or iSCPs without the aid of transcription factors (75, 96, 97). However, further elucidation of the molecular mechanisms and functional validation of these cells will be required. Recently, the establishment of organoids which mimic natural stimuli for tissue development, including cell-cell interactions, are at the forefront of stem cell research. Obtaining functional brain organoids in which mature glial cells are present is an extremely difficult challenge that is drawing considerable attention nowadays within the stem cell field (98). As mentioned earlier, the limitation of the glial differentiation, which appears late in development, is still not overcome, even in brain organoids. Brain organoids do not contain qualified glial cells even after hundreds of days of differentiation, even though the neuronal cells are observed in the early stages of organoids (99). Although long-term cultivation of brain organoids has reported the appearance of oligodendrocytes, these are often atypical populations that are not present in normal brain condition such oligodendrocyte spheroids (100). This highlights the feasibility of the direct conversion method as an alternative to overcome the difficulties of the differentiation methods. Therefore, future studies that combine direct conversion-derived mature glial cells with organoids will provide diverse understanding and new insights across the fields of development, aging, physiology, and pathology (101). However, of course, how to combine the brain organoids generated by the development process and the glia with relative maturity is still challenging.

Conclusions

Since glia are one of the major populations of the nervous system and exert a variety of roles that support the structural and functional homeostasis of nervous tissue, it is crucial to include the roles of glial cells to understand in physiological neurobiology and pathological studies in neural system. A direct conversion method has been proposed as an alternative to the differentiation from hPSCs. Although the direct conversion method still has multiple challenges requiring methodological improvements, it provides an opportunity to understand the pathophysiology of the nervous system with advantages of mature and functional oligodendrocytes and Schwann cells.

Acknowledgments

Work in Lee lab was supported by grants from the National Institutes of Health through R01NS093213. Work in Kim lab was supported by grants from the NRF grant funded by the Korea government (NRF-2017R1C1B 3009321 and NRF-2021M3E5E5096744).

Potential Conflict of Interest

The authors have no conflicting financial interest.

Author Contributions

W.Y., Y.J.K.: collecting data, writing manuscript, G.L.: conception, collecting data, and writing manuscript.

References
  1. von Bartheld CS. Myths and truths about the cellular composition of the human brain: a review of influential concepts. J Chem Neuroanat 2018;93:2-15.
    Pubmed KoreaMed CrossRef
  2. Verkhratsky A, Orkand RK, Kettenmann H. Glial calcium: homeostasis and signaling function. Physiol Rev 1998;78:99-141.
    Pubmed CrossRef
  3. Bennett ML, Viaene AN. What are activated and reactive glia and what is their role in neurodegeneration? Neurobiol Dis. 2021;148:105172.
    Pubmed CrossRef
  4. Kettenmann H, Ransom BR. Neuroglia. 3rd ed. New York: Oxford University Press; 2013. 930.
  5. Hu BY, Du ZW, Li XJ, Ayala M, Zhang SC. Human oligodendrocytes from embryonic stem cells: conserved SHH signaling networks and divergent FGF effects. Development 2009;136:1443-1452.
    Pubmed KoreaMed CrossRef
  6. Shaltouki A, Peng J, Liu Q, Rao MS, Zeng X. Efficient generation of astrocytes from human pluripotent stem cells in defined conditions. Stem Cells 2013;31:941-952.
    Pubmed CrossRef
  7. Mukherjee-Clavin B, Mi R, Kern B, Choi IY, Lim H, Oh Y, Lannon B, Kim KJ, Bell S, Hur JK, Hwang W, Che YH, Habib O, Baloh RH, Eggan K, Brandacher G, Hoke A, Studer L, Kim YJ, Lee G. Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder. Nat Biomed Eng 2019;3:571-582.
    Pubmed KoreaMed CrossRef
  8. Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 2006;30:718-729.
    Pubmed CrossRef
  9. Jakovcevski I, Filipovic R, Mo Z, Rakic S, Zecevic N. Oligodendrocyte development and the onset of myelination in the human fetal brain. Front Neuroanat 2009;3:5.
    Pubmed KoreaMed CrossRef
  10. Shearman JD, Franks AJ. S-100 protein in Schwann cells of the developing human peripheral nerve. An immunohistochemical study. Cell Tissue Res 1987;249:459-463.
    Pubmed CrossRef
  11. Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology 2010;35:147-168.
    Pubmed KoreaMed CrossRef
  12. Lanjewar SN, Sloan SA. Growing glia: cultivating human stem cell models of gliogenesis in health and disease. Front Cell Dev Biol. 2021;9:649538.
    Pubmed KoreaMed CrossRef
  13. Imaizumi Y, Okano H. Modeling human neurological disorders with induced pluripotent stem cells. J Neurochem 2014;129:388-399.
    Pubmed CrossRef
  14. Horisawa K, Suzuki A. Direct cell-fate conversion of somatic cells: toward regenerative medicine and industries. Proc Jpn Acad Ser B Phys Biol Sci 2020;96:131-158.
    Pubmed KoreaMed CrossRef
  15. Mitchell R, Szabo E, Shapovalova Z, Aslostovar L, Makondo K, Bhatia M. Molecular evidence for OCT4-induced plasticity in adult human fibroblasts required for direct cell fate conversion to lineage specific progenitors. Stem Cells 2014;32:2178-2187.
    Pubmed CrossRef
  16. Kim YJ, Lim H, Li Z, Oh Y, Kovlyagina I, Choi IY, Dong X, Lee G. Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. Cell Stem Cell 2014;15:497-506.
    Pubmed CrossRef
  17. Chang Y, Cho B, Kim S, Kim J. Direct conversion of fibroblasts to osteoblasts as a novel strategy for bone regeneration in elderly individuals. Exp Mol Med 2019;51:1-8.
    Pubmed KoreaMed CrossRef
  18. Carlson BM. The human body: linking structure and function. London: Elsevier/Academic Press; 2019. 55.
  19. Jessen KR. Glial cells. Int J Biochem Cell Biol 2004;36:1861-1867.
    Pubmed CrossRef
  20. Jäkel S, Dimou L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci 2017;11:24.
    Pubmed KoreaMed CrossRef
  21. Jessen KR, Mirsky R. The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 2005;6:671-682.
    Pubmed CrossRef
  22. Kurosinski P, Götz J. Glial cells under physiologic and pathologic conditions. Arch Neurol 2002;59:1524-1528.
    Pubmed CrossRef
  23. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 2020;21:139-152.
    Pubmed CrossRef
  24. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:309-316.
    Pubmed CrossRef
  25. Visser VL, Rusinek H, Weickenmeier J. Peak ependymal cell stretch overlaps with the onset locations of periventricular white matter lesions. Sci Rep. 2021;11:21956.
    Pubmed KoreaMed CrossRef
  26. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell 1999;96:25-34.
    CrossRef
  27. Carlén M, Meletis K, Göritz C, Darsalia V, Evergren E, Tanigaki K, Amendola M, Barnabé-Heider F, Yeung MS, Naldini L, Honjo T, Kokaia Z, Shupliakov O, Cassidy RM, Lindvall O, Frisén J. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci 2009;12:259-267.
    Pubmed CrossRef
  28. Wei D, Levic S, Nie L, Gao WQ, Petit C, Jones EG, Yamoah EN. Cells of adult brain germinal zone have properties akin to hair cells and can be used to replace inner ear sensory cells after damage. Proc Natl Acad Sci U S A 2008;105:21000-21005.
    Pubmed KoreaMed CrossRef
  29. Salzer JL, Zalc B. Myelination. Curr Biol 2016;26:R971-R975.
    Pubmed KoreaMed CrossRef
  30. Bolívar S, Navarro X, Udina E. Schwann cell role in selectivity of nerve regeneration. Cells 2020;9:2131.
    Pubmed KoreaMed CrossRef
  31. Love S. Demyelinating diseases. J Clin Pathol 2006;59:1151-1159.
    Pubmed KoreaMed CrossRef
  32. Höftberger R, Guo Y, Flanagan EP, Lopez-Chiriboga AS, Endmayr V, Hochmeister S, Joldic D, Pittock SJ, Tillema JM, Gorman M, Lassmann H, Lucchinetti CF. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol 2020;139:875-892.
    Pubmed KoreaMed CrossRef
  33. Park HT, Kim YH, Lee KE, Kim JK. Behind the pathology of macrophage-associated demyelination in inflammatory neuropathies: demyelinating Schwann cells. Cell Mol Life Sci 2020;77:2497-2506.
    Pubmed KoreaMed CrossRef
  34. Ydens E, Lornet G, Smits V, Goethals S, Timmerman V, Janssens S. The neuroinflammatory role of Schwann cells in disease. Neurobiol Dis 2013;55:95-103.
    Pubmed CrossRef
  35. Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 2014;141:302-313.
    Pubmed KoreaMed CrossRef
  36. van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ, Rowitch DH, Nijboer CH. Origin and dynamics of oligodendrocytes in the developing brain: implications for perinatal white matter injury. Glia 2018;66:221-238.
    Pubmed KoreaMed CrossRef
  37. Najm FJ, Zaremba A, Caprariello AV, Nayak S, Freundt EC, Scacheri PC, Miller RH, Tesar PJ. Rapid and robust generation of functional oligodendrocyte progenitor cells from epiblast stem cells. Nat Methods 2011;8:957-962.
    Pubmed KoreaMed CrossRef
  38. Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, Maherali N, Studer L, Hochedlinger K, Windrem M, Goldman SA. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013;12:252-264.
    Pubmed KoreaMed CrossRef
  39. Stacpoole SR, Spitzer S, Bilican B, Compston A, Karadottir R, Chandran S, Franklin RJ. High yields of oligodendrocyte lineage cells from human embryonic stem cells at physiological oxygen tensions for evaluation of translational biology. Stem Cell Reports 2013;1:437-450.
    Pubmed KoreaMed CrossRef
  40. Piao J, Major T, Auyeung G, Policarpio E, Menon J, Droms L, Gutin P, Uryu K, Tchieu J, Soulet D, Tabar V. Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell 2015;16:198-210.
    Pubmed KoreaMed CrossRef
  41. Yun W, Hong W, Son D, Liu HW, Kim SS, Park M, Kim IY, Kim DS, Song G, You S. Generation of anterior hindbrain-specific, glial-restricted progenitor-like cells from human pluripotent stem cells. Stem Cells Dev 2019;28:633-648.
    Pubmed CrossRef
  42. Douvaras P, Fossati V. Generation and isolation of oligodendrocyte progenitor cells from human pluripotent stem cells. Nat Protoc 2015;10:1143-1154.
    Pubmed CrossRef
  43. Douvaras P, Wang J, Zimmer M, Hanchuk S, O'Bara MA, Sadiq S, Sim FJ, Goldman J, Fossati V. Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports 2014;3:250-259.
    Pubmed KoreaMed CrossRef
  44. Yamashita T, Miyamoto Y, Bando Y, Ono T, Kobayashi S, Doi A, Araki T, Kato Y, Shirakawa T, Suzuki Y, Yamauchi J, Yoshida S, Sato N. Differentiation of oligodendrocyte progenitor cells from dissociated monolayer and feeder-free cultured pluripotent stem cells. PLoS One. 2017;12:e0171947.
    Pubmed KoreaMed CrossRef
  45. Kim DS, Jung SJ, Lee JS, Lim BY, Kim HA, Yoo JE, Kim DW, Leem JW. Rapid generation of OPC-like cells from human pluripotent stem cells for treating spinal cord injury. Exp Mol Med. 2017;49:e361.
    Pubmed KoreaMed CrossRef
  46. Ehrlich M, Mozafari S, Glatza M, Starost L, Velychko S, Hallmann AL, Cui QL, Schambach A, Kim KP, Bachelin C, Marteyn A, Hargus G, Johnson RM, Antel J, Sterneckert J, Zaehres H, Schöler HR, Baron-Van Evercooren A, Kuhlmann T. Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors. Proc Natl Acad Sci U S A 2017;114:E2243-E2252.
    Pubmed KoreaMed CrossRef
  47. García-León JA, Kumar M, Boon R, Chau D, One J, Wolfs E, Eggermont K, Berckmans P, Gunhanlar N, de Vrij F, Lendemeijer B, Pavie B, Corthout N, Kushner SA, Dávila JC, Lambrichts I, Hu WS, Verfaillie CM. SOX10 single transcription factor-based fast and efficient generation of oligodendrocytes from human pluripotent stem cells. Stem Cell Reports 2018;10:655-672.
    Pubmed KoreaMed CrossRef
  48. Wang J, Pol SU, Haberman AK, Wang C, O'Bara MA, Sim FJ. Transcription factor induction of human oligodendrocyte progenitor fate and differentiation. Proc Natl Acad Sci U S A 2014;111:E2885-E2894.
    Pubmed KoreaMed CrossRef
  49. Schmitteckert S, Ziegler C, Rappold GA, Niesler B, Rolletschek A. Molecular characterization of embryonic stem cell-derived cardiac neural crest-like cells revealed a spatiotemporal expression of an Mlc-3 isoform. Int J Stem Cells 2020;13:65-79.
    Pubmed KoreaMed CrossRef
  50. Soldatov R, Kaucka M, Kastriti ME, Petersen J, Chontorotzea T, Englmaier L, Akkuratova N, Yang Y, Häring M, Dyachuk V, Bock C, Farlik M, Piacentino ML, Boismoreau F, Hilscher MM, Yokota C, Qian X, Nilsson M, Bronner ME, Croci L, Hsiao WY, Guertin DA, Brunet JF, Consalez GG, Ernfors P, Fried K, Kharchenko PV, Adameyko I. Spatiotemporal structure of cell fate decisions in murine neural crest. Science. 2019;364:eaas9536.
    Pubmed CrossRef
  51. Wilson YM, Richards KL, Ford-Perriss ML, Panthier JJ, Murphy M. Neural crest cell lineage segregation in the mouse neural tube. Development 2004;131:6153-6162.
    Pubmed CrossRef
  52. Achilleos A, Trainor PA. Neural crest stem cells: discovery, properties and potential for therapy. Cell Res 2012;22:288-304.
    Pubmed KoreaMed CrossRef
  53. Le Douarin NM. The avian embryo as a model to study the development of the neural crest: a long and still ongoing story. Mech Dev 2004;121:1089-1102.
    Pubmed CrossRef
  54. Lee G, Kim H, Elkabetz Y, Al Shamy G, Panagiotakos G, Barberi T, Tabar V, Studer L. Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nat Biotechnol 2007;25:1468-1475. Erratum in: Nat Biotechnol 2008;26:831.
    Pubmed CrossRef
  55. Lee G, Chambers SM, Tomishima MJ, Studer L. Derivation of neural crest cells from human pluripotent stem cells. Nat Protoc 2010;5:688-701.
    Pubmed CrossRef
  56. Monje PV. Schwann cell cultures: biology, technology and therapeutics. Cells 2020;9:1848.
    Pubmed KoreaMed CrossRef
  57. Huang CW, Huang WC, Qiu X, Fernandes Ferreira da Silva F, Wang A, Patel S, Nesti LJ, Poo MM, Li S. The differentiation stage of transplanted stem cells modulates nerve regeneration. Sci Rep. 2017;7:17401.
    Pubmed KoreaMed CrossRef
  58. Kreitzer FR, Salomonis N, Sheehan A, Huang M, Park JS, Spindler MJ, Lizarraga P, Weiss WA, So PL, Conklin BR. A robust method to derive functional neural crest cells from human pluripotent stem cells. Am J Stem Cells 2013;2:119-131.
    Pubmed KoreaMed
  59. Liu Q, Spusta SC, Mi R, Lassiter RN, Stark MR, Höke A, Rao MS, Zeng X. Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional schwann cells. Stem Cells Transl Med 2012;1:266-278.
    Pubmed KoreaMed CrossRef
  60. Wang A, Tang Z, Park IH, Zhu Y, Patel S, Daley GQ, Li S. Induced pluripotent stem cells for neural tissue engineering. Biomaterials 2011;32:5023-5032.
    Pubmed KoreaMed CrossRef
  61. Ziegler L, Grigoryan S, Yang IH, Thakor NV, Goldstein RS. Efficient generation of schwann cells from human embryonic stem cell-derived neurospheres. Stem Cell Rev Rep 2011;7:394-403.
    Pubmed CrossRef
  62. Kim HS, Lee J, Lee DY, Kim YD, Kim JY, Lim HJ, Lim S, Cho YS. Schwann cell precursors from human pluripotent stem cells as a potential therapeutic target for myelin repair. Stem Cell Reports 2017;8:1714-1726.
    Pubmed KoreaMed CrossRef
  63. Huang Z, Powell R, Phillips JB, Haastert-Talini K. Perspective on Schwann cells derived from induced pluripotent stem cells in peripheral nerve tissue engineering. Cells 2020;9:2497.
    Pubmed KoreaMed CrossRef
  64. Hopf A, Schaefer DJ, Kalbermatten DF, Guzman R, Madduri S. Schwann cell-like cells: origin and usability for repair and regeneration of the peripheral and central nervous system. Cells 2020;9:1990.
    Pubmed KoreaMed CrossRef
  65. Papp B, Plath K. Epigenetics of reprogramming to induced pluripotency. Cell 2013;152:1324-1343.
    Pubmed KoreaMed CrossRef
  66. Guo G, von Meyenn F, Rostovskaya M, Clarke J, Dietmann S, Baker D, Sahakyan A, Myers S, Bertone P, Reik W, Plath K, Smith A. Epigenetic resetting of human pluripotency. Development 2017;144:2748-2763. Erratum in: Development 2018;145:dev166397.
    Pubmed KoreaMed CrossRef
  67. Berdasco M, Esteller M. DNA methylation in stem cell renewal and multipotency. Stem Cell Res Ther 2011;2:42.
    Pubmed KoreaMed CrossRef
  68. Papp B, Plath K. Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res 2011;21:486-501.
    Pubmed KoreaMed CrossRef
  69. Wu H, Sun YE. Epigenetic regulation of stem cell differentiation. Pediatr Res 2006;59(4 Pt 2):21R-25R.
    Pubmed CrossRef
  70. Najm FJ, Lager AM, Zaremba A, Wyatt K, Caprariello AV, Factor DC, Karl RT, Maeda T, Miller RH, Tesar PJ. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat Biotechnol 2013;31:426-433.
    Pubmed KoreaMed CrossRef
  71. Yang N, Zuchero JB, Ahlenius H, Marro S, Ng YH, Vierbuchen T, Hawkins JS, Geissler R, Barres BA, Wernig M. Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol 2013;31:434-439.
    Pubmed KoreaMed CrossRef
  72. Kim JB, Lee H, Araúzo-Bravo MJ, Hwang K, Nam D, Park MR, Zaehres H, Park KI, Lee SJ. Oct4-induced oligodendrocyte progenitor cells enhance functional recovery in spinal cord injury model. EMBO J 2015;34:2971-2983.
    Pubmed KoreaMed CrossRef
  73. Mokhtarzadeh Khanghahi A, Satarian L, Deng W, Baharvand H, Javan M. In vivo conversion of astrocytes into oligodendrocyte lineage cells with transcription factor Sox10; promise for myelin repair in multiple sclerosis. PLoS One. 2018;13:e0203785.
    Pubmed KoreaMed CrossRef
  74. Farhangi S, Dehghan S, Totonchi M, Javan M. In vivo conversion of astrocytes to oligodendrocyte lineage cells in adult mice demyelinated brains by Sox2. Mult Scler Relat Disord 2019;28:263-272.
    Pubmed CrossRef
  75. Liu C, Hu X, Li Y, Lu W, Li W, Cao N, Zhu S, Cheng J, Ding S, Zhang M. Conversion of mouse fibroblasts into oligodendrocyte progenitor-like cells through a chemical approach. J Mol Cell Biol 2019;11:489-495.
    Pubmed KoreaMed CrossRef
  76. Weider M, Wegener A, Schmitt C, Küspert M, Hillgärtner S, Bösl MR, Hermans-Borgmeyer I, Nait-Oumesmar B, Wegner M. Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells. PLoS Genet. 2015;11:e1005008.
    Pubmed KoreaMed CrossRef
  77. Yun W, Choi KA, Hwang I, Zheng J, Park M, Hong W, Jang AY, Kim JH, Choi W, Kim DS, Kim IY, Kim YJ, Liu Y, Yoon BS, Park G, Song G, Hong S, You S. OCT4-induced oligodendrocyte progenitor cells promote remyelination and ameliorate disease. NPJ Regen Med 2022;7:4.
    Pubmed KoreaMed CrossRef
  78. King HW, Klose RJ. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. Elife. 2017;6:e22631.
    Pubmed KoreaMed CrossRef
  79. Soufi A, Garcia MF, Jaroszewicz A, Osman N, Pellegrini M, Zaret KS. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 2015;161:555-568.
    Pubmed KoreaMed CrossRef
  80. Dehghan S, Hesaraki M, Soleimani M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M. Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice. Neuroscience 2016;318:178-189.
    Pubmed CrossRef
  81. Matjusaitis M, Wagstaff LJ, Martella A, Baranowski B, Blin C, Gogolok S, Williams A, Pollard SM. Reprogramming of fibroblasts to oligodendrocyte progenitor-like cells using CRISPR/Cas9-based synthetic transcription factors. Stem Cell Reports 2019;13:1053-1067.
    Pubmed KoreaMed CrossRef
  82. Sowa Y, Kishida T, Tomita K, Yamamoto K, Numajiri T, Mazda O. Direct conversion of human fibroblasts into Schwann cells that facilitate regeneration of injured peripheral nerve in vivo. Stem Cells Transl Med 2017;6:1207-1216.
    Pubmed KoreaMed CrossRef
  83. Mazzara PG, Massimino L, Pellegatta M, Ronchi G, Ricca A, Iannielli A, Giannelli SG, Cursi M, Cancellieri C, Sessa A, Del Carro U, Quattrini A, Geuna S, Gritti A, Taveggia C, Broccoli V. Two factor-based reprogramming of rodent and human fibroblasts into Schwann cells. Nat Commun. 2017;8:14088.
    Pubmed KoreaMed CrossRef
  84. Jang SW, Svaren J. Induction of myelin protein zero by early growth response 2 through upstream and intragenic elements. J Biol Chem 2009;284:20111-20120.
    Pubmed KoreaMed CrossRef
  85. LeBlanc SE, Ward RM, Svaren J. Neuropathy-associated Egr2 mutants disrupt cooperative activation of myelin protein zero by Egr2 and Sox10. Mol Cell Biol 2007;27:3521-3529.
    Pubmed KoreaMed CrossRef
  86. Kim HS, Kim JY, Song CL, Jeong JE, Cho YS. Directly induced human Schwann cell precursors as a valuable source of Schwann cells. Stem Cell Res Ther 2020;11:257.
    Pubmed KoreaMed CrossRef
  87. Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF, Kirsch IR, McBride OW, Bertness V, Hollis GF, Minna JD. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature 1985;318:69-73.
    Pubmed CrossRef
  88. Peng S, Maihle NJ, Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene 2010;29:2153-2159.
    Pubmed CrossRef
  89. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, Kim SY, Wardwell L, Tamayo P, Gat-Viks I, Ramos AH, Woo MS, Weir BA, Getz G, Beroukhim R, O'Kelly M, Dutt A, Rozenblatt-Rosen O, Dziunycz P, Komisarof J, Chirieac LR, Lafargue CJ, Scheble V, Wilbertz T, Ma C, Rao S, Nakagawa H, Stairs DB, Lin L, Giordano TJ, Wagner P, Minna JD, Gazdar AF, Zhu CQ, Brose MS, Cecconello I, Ribeiro U Jr, Marie SK, Dahl O, Shivdasani RA, Tsao MS, Rubin MA, Wong KK, Regev A, Hahn WC, Beer DG, Rustgi AK, Meyerson M. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 2009;41:1238-1242.
    Pubmed KoreaMed CrossRef
  90. Kilmister EJ, Patel J, Bockett N, Chang-McDonald B, Sim D, Wickremesekera A, Davis PF, Tan ST. Embryonic stem cell-like subpopulations are present within Schwannoma. J Clin Neurosci 2020;81:201-209.
    Pubmed CrossRef
  91. Kristensen BW, Priesterbach-Ackley LP, Petersen JK, Wesseling P. Molecular pathology of tumors of the central nervous system. Ann Oncol 2019;30:1265-1278.
    Pubmed KoreaMed CrossRef
  92. Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci 2000;910:121-137; discussion 137-139.
    Pubmed CrossRef
  93. LeBleu VS, Neilson EG. Origin and functional heterogeneity of fibroblasts. FASEB J 2020;34:3519-3536.
    Pubmed CrossRef
  94. Mateu R, Živicová V, Krejčí ED, Grim M, Strnad H, Vlček Č, Kolář M, Lacina L, Gál P, Borský J, Smetana K Jr, Dvořánková B. Functional differences between neonatal and adult fibroblasts and keratinocytes: donor age affects epithelial-mesenchymal crosstalk in vitro. Int J Mol Med 2016;38:1063-1074.
    Pubmed KoreaMed CrossRef
  95. Chipev CC, Simon M. Phenotypic differences between dermal fibroblasts from different body sites determine their responses to tension and TGFbeta1. BMC Dermatol 2002;2:13.
    Pubmed KoreaMed CrossRef
  96. Thoma EC. Chemical conversion of human fibroblasts into functional Schwann cells. Methods Mol Biol 2018;1739:127-136.
    Pubmed CrossRef
  97. Kitada M, Murakami T, Wakao S, Li G, Dezawa M. Direct conversion of adult human skin fibroblasts into functional Schwann cells that achieve robust recovery of the severed peripheral nerve in rats. Glia 2019;67:950-966.
    Pubmed CrossRef
  98. Porciúncula LO, Goto-Silva L, Ledur PF, Rehen SK. The age of brain organoids: tailoring cell identity and functionality for normal brain development and disease modeling. Front Neurosci. 2021;15:674563.
    Pubmed KoreaMed CrossRef
  99. Kim J, Sullivan GJ, Park IH. How well do brain organoids capture your brain? iScience. 2021;24:102063.
    Pubmed KoreaMed CrossRef
  100. Marton RM, Miura Y, Sloan SA, Li Q, Revah O, Levy RJ, Huguenard JR, Pașca SP. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat Neurosci 2019;22:484-491.
    Pubmed KoreaMed CrossRef
  101. Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, Yeromin AV, Scarfone VM, Marsh SE, Fimbres C, Caraway CA, Fote GM, Madany AM, Agrawal A, Kayed R, Gylys KH, Cahalan MD, Cummings BJ, Antel JP, Mortazavi A, Carson MJ, Poon WW, Blurton-Jones M. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 2017;94:278-293.e9.
    Pubmed KoreaMed CrossRef