Prevalence and Distribution of Diffuse Idiopathic Skeletal Hyperostosis on Whole-spine Computed Tomography in Patients With Cervical Ossification of the Posterior Longitudinal Ligament: A Multicenter Study.

STUDY DESIGN: This was a retrospective multicenter study. OBJECTIVE: To clarify the progression of diffuse idiopathic skeletal hyperostosis (DISH) using whole-spine computed tomography in patients with cervical ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: DISH and cervical OPLL frequently coexist, and can cause ankylosing spinal fractures due to biomechanical changes and fragility of the affected vertebrae. The epidemiology and pathophysiology of DISH occurring with cervical OPLL are unclear. MATERIALS AND METHODS: We used whole-spine computed tomography to determine the prevalence of DISH in 234 patients with a diagnosis of cervical OPLL based on plain cervical radiographs. We established a novel system for grading the progression of DISH based on a cluster analysis of the DISH distribution along the spine. We calculated the correlation coefficient between this grading system and patient age. RESULTS: The prevalence of DISH in patients with cervical OPLL was 48.7%. Patients with DISH were significantly older than those who did not have DISH (67.3 vs. 63.4 y; P=0.005). Cluster analysis classified the DISH distribution into 6 regions, based on the levels affected: C2-C5, C3-T1, C6-T5, T3-10, T8-L2, and T12-S1. DISH was observed most frequently at T3-T10. We defined a system for grading DISH progression based on the number of regions involved, from grade 0 to 6. DISH was distributed at T3-T10 in >60% of the grade 1 patients, whereas most patients with DISH at the cervical or lumbar spine were grade 4 or 5. There was a weak but significant correlation between the DISH grade and patient age. CONCLUSIONS: DISH was present in nearly half of the patients with cervical OPLL. DISH was more common in older patients. DISH developed at the thoracic level and progressed into the cervical and/or lumbar spine with age. LEVEL OF EVIDENCE: Level III.

Lumbar spine epidural abscess and facet joint septic arthritis due to Streptococcus agalactiae: a case report.

BACKGROUND: Here we report a rare case of lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae, which had spread to the iliopsoas muscles, leading to urine retention. CASE PRESENTATION: A 68-year-old woman with low back pain experienced a sudden onset of bilateral lower limb weakness, it was followed 14 days later by urine retention. At consultation, magnetic resonance imaging and identification of serum ß-hemolytic streptococci provided a diagnosis of Streptococcus agalactiae infection. She was started on antibiotics. Despite diminishing signs of inflammation, preoperative MRI showed an epidural mass at T12-L4 compressing the cord and involving the paravertebral muscles as well. Group B beta-hemolytic streptococci were detected in both urine and blood. Because of bilateral lower limb weakness and urine retention, T12-L4 hemilaminectomy was performed. The L3/L4 intertransverse ligament resected and abscess drained. Histopathology revealed that inflammatory cells had invaded the facet joint. Group B beta-hemolytic streptococci were identified, confirming the diagnosis. The patient continued with the antibiotics postoperatively, and her health rapidly improved. CONCLUSION: Lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae is a clinical emergency, with significant morbidity and mortality especially with delayed diagnosis. A delay in both diagnosis and aggressive treatment can lead to not only severe neurological deficit but also to septicaemia, multiorgan failure, and even death.

Hypertrophic spinal pachymeningitis associated with human T-cell lymphotrophic virus-1 infection and Sjogren's syndrome: A case report and brief literature review.

INTRODUCTION: Reports of hypertrophic spinal pachymeningitis associated with human T-cell lymphotrophic virus-1 (HTLV-1) infection and Sjogren's syndrome in the English literature are still very rare. PRESENTATION OF CASE: We hereby present a case of a 78-year-old female with a history of lower extremity weakness after a fall, which fully resolved after conservative treatment. However, the symptoms recurred 4 years later, and the patient became unable to walk. The patient had no superficial or deep sensation below the level of T9, and she also had urinary retention. Magnetic resonance imaging showed that hypertrophic dura mater was compressing the spinal cord from T2 to T10. Blood testing revealed increased anti-HTLV-1 antibody, rheumatoid factor, elevation of anti-SS-A antibody and antinuclear antibody. The cerebrospinal fluid contained markedly elevated levels of total protein and cell numbers. Biopsy of the labial gland of the lip revealed chronic sialadenitis. DISCUSSION: In collaboration with a neurologist, we diagnosed this patient with hypertrophic spinal pachymeningitis associated with HTLV-1 infection and Sjogren's syndrome. We performed laminectomy at the affected spinal levels, resected the thickened dura, and maintained the patient on steroid therapy. The patient attained a marked recovery; she could walk with a cane and her urinary retention was improved. CONCLUSION: For the management of HSP associated with HTLV-1 and SS, we recommend surgical decompression with subsequent prolonged steroid therapy and prolonged close monitoring to achieve a good long-term outcome.

Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750.

Risk Factors for Postoperative Ileus after Scoliosis Surgery.

INTRODUCTION: One complication after scoliosis surgery is ileus; however, few reports have described the frequency of and risk factors for this complication. We conducted a retrospective clinical study with logistic regression analysis to confirm the frequency of and risk factors for ileus after scoliosis surgery. METHODS: After a retrospective review of data from patients who underwent surgical correction of spinal deformity from 2009 to 2014, 110 cases (age range, 4-73 yr; median, 14 yr) were included in the study. We defined postoperative ileus (POI) as a surgical complication characterized by decreased intestinal peristalsis and the absence of stool for more than 3 days postoperatively. Various parameters were compared between patients with POI and those without POI. Logistic regression analysis was performed to assess the risk factors associated with ileus; a P value of <0.05 was considered statistically significant. RESULTS: Fifteen of 110 (13.6%) cases developed POI. The median height, weight, operation time, and blood loss volume of the patients with versus without POI were 146 versus 152 cm, 39.0 versus 44.0 kg, 387 versus 359 min, and 1590 versus 1170 g, respectively. There were no significant differences between patients with versus without POI in the measured parameters, with the exception of patient height, bed rest period, and presence of neuromuscular scoliosis. Multiple logistic regression analysis revealed neuromuscular scoliosis as a significant risk factor for POI (odds ratio, 4.21; 95% CI, 1.23-14.40). CONCLUSIONS: Our findings indicate a high probability of POI after scoliosis surgery, with an incidence of 13.6%. Neurogenic scoliosis, but not lowest instrumented vertebra or correction rate, was a risk factor for POI after scoliosis surgery. Digestive symptoms should be carefully monitored after surgery, particularly in patients with neuromuscular scoliosis.

Risk factors for unavoidable removal of instrumentation after surgical site infection of spine surgery: A retrospective case-control study.

Surgical site infection (SSI) after spine instrumentation is difficult to treat, and often requires removal of instrumentation. The removal of instrumentation after spine surgery is a severe complication that can lead to the deterioration of activities of daily living and poor prognosis. Although there are many reports on SSI after spine surgery, few reports have investigated the risk factors for the removal of instrumentation after spine surgery SSI. This study aimed to identify the risk factors for unavoidable removal of instrumentation after SSI of spine surgery. We retrospectively reviewed 511 patients who underwent spine surgery with instrumentation at Kagoshima University Hospital from January 2006 to December 2014. Risk factors associated with SSI were analyzed via multiple logistic regression analysis. Parameters of the group that needed instrumentation removal were compared with the group that did not require instrumentation removal using the Mann-Whitney U and Fisher's exact tests. The posterior approach was used in most cases (453 of 511 cases, 88.6%). SSI occurred in 16 of 511 cases (3.14%) of spine surgery with instrumentation. Multivariate logistic regression analysis identified 2 significant risk factors for SSI: operation time, and American Society of Anesthesiologists physical status classification ≥ 3. Twelve of the 16 patients with SSI (75%) were able to keep the instrumentation after SSI. Pseudarthrosis occurred in 2 of 4 cases (50%) after instrumentation removal. Risk factors identified for instrumentation removal after spine SSI were a greater number of past surgeries, low preoperative hemoglobin, high preoperative creatinine, high postoperative infection treatment score for the spine, and the presence of methicillin-resistant Staphylococcus aureus. In these high risk cases, attempts should be made to decrease the risk factors preoperatively, and careful postoperative monitoring should be conducted.

Retro-odontoid mass without atlantoaxial instability causing cervical myelopathy: a case report of transdural surgical resection.

INTRODUCTION: Retro-odontoid mass rarely occur in patients with noninflammatory retro-odontoid lesions without atlantoaxial instability. We describe a rare case of retro-odontoid mass without atlantoaxial instability operated on by a transdural approach. CASE PRESENTATION: The patient was an 83-year-old man who presented with a retro-odontoid mass causing symptomatic cervical myelopathy. Preoperative magnetic resonance imaging (MRI) revealed that the mass was severely compressing the spinal cord. We operated on it via a C1 laminectomy and performed tumor resection by a transdural approach. Pathological findings from the operative specimen confirmed the diagnosis; histopathological examination revealed that the mass contained fibrinoid material, and collagenous tissue with myxoid changes, but no granulation or a granulomatous lesion. Postoperative MRI confirmed spinal cord decompression. The patient's symptoms were alleviated, and he has not had a recurrence or cervical instability in the 7 years since his surgery. DISCUSSION: We successfully used a transdural approach in the present case and have observed no recurrence for 7 years postoperatively. C1 laminectomy is reportedly beneficial, especially for elderly patients, given the risk of other surgical options using an anterior transoral approach or posterior fusion. However, most tumors do not attenuate after C1 laminectomy alone; hence, we think that tumor resection by the transdural approach is one effective method to perform enucleation of the tumor after C1 laminectomy.

Risk factors for venous thromboembolism after spine surgery.

The efficacy and safety of chemical prophylaxis to prevent the development of deep venous thrombosis (DVT) or pulmonary embolism (PE) following spine surgery are controversial because of the possibility of epidural hematoma formation. Postoperative venous thromboembolism (VTE) after spine surgery occurs at a frequency similar to that seen after joint operations, so it is important to identify the risk factors for VTE formation following spine surgery. We therefore retrospectively studied data from patients who had undergone spinal surgery and developed postoperative VTE to identify those risk factors. We conducted a retrospective clinical study with logistic regression analysis of a group of 80 patients who had undergone spine surgery at our institution from June 2012 to August 2013. All patients had been screened by ultrasonography for DVT in the lower extremities. Parameters of the patients with VTE were compared with those without VTE using the Mann-Whitney U-test and Fisher exact probability test. Logistic regression analysis was used to analyze the risk factors associated with VTE. A value of P < 0.05 was used to denote statistical significance. The prevalence of VTE was 25.0% (20/80 patients). One patient had sensed some incongruity in the chest area, but the vital signs of all patients were stable. VTEs had developed in the pulmonary artery in one patient, in the superficial femoral vein in one patient, in the popliteal vein in two patients, and in the soleal vein in 18 patients. The Mann-Whitney U-test and Fisher exact probability test showed that, except for preoperative walking disability, none of the parameters showed a significant difference between patients with and without VTE. Risk factors identified in the multivariate logistic regression analysis were preoperative walking disability and age. The prevalence of VTE after spine surgery was relatively high. The most important risk factor for developing postoperative VTE was preoperative walking disability. Gait training during the early postoperative period is required to prevent VTE.

GLI2 is a novel therapeutic target for metastasis of osteosarcoma.

Aberrant activation of the Hedgehog (Hh) pathway has been reported in several malignancies. We previously demonstrated that knockdown of GLI2 inhibited proliferation of osteosarcoma cells through regulation of the cell cycle. In this study, we analyzed the function of GLI2 in the pathogenesis of osteosarcoma metastasis. Immunohistochemical studies showed that GLI2 was overexpressed in patient osteosarcoma specimens. Knockdown of GLI2 inhibited migration and invasion of osteosarcoma cells. In contrast, the forced expression of constitutively active GLI2 in mesenchymal stem cells promoted invasion. In addition, xenograft models showed that knockdown of GLI2 decreased lung metastasis of osteosarcomas. To examine clinical applications, we evaluated the efficacy of arsenic trioxide (ATO), which is a Food and Drug Administration-approved antitumor drug, on osteosarcoma cells. ATO treatment suppressed the invasiveness of osteosarcoma cells by inhibiting the transcriptional activity of GLI2. In addition, the combination of Hh inhibitors including ATO, vismodegib and GANT61 prevented migration and metastasis of osteosarcoma cells. Consequently, our findings suggested that GLI2 regulated metastasis as well as the progression of osteosarcomas. Inhibition of the GLI2 transcription may be an effective therapeutic method for preventing osteosarcoma metastasis.

Metastatic bone tumors: Analysis of factors affecting prognosis and efficacy of CT and 18F-FDG PET-CT in identifying primary lesions.

We analyzed the prognostic factors in patients with metastatic bone tumors and evaluated the efficacy of different modalities in identifying the primary lesions. A total of 145 patients with bone metastases who attended the orthopaedic outpatient clinic were included in this study. The most frequent site of bone metastases was the spine. The primary tumor type was differently distributed between patients with a known primary tumor at the first visit and those with an unknown primary lesion. The number of breast cancer cases was statistically significantly lower in the primary-unknown group. However, the number of myeloma cases was significantly higher in the primary-unknown group. Survival was significantly lower in the skeletal-related events (SREs) compared to that in the non-SREs group. Furthermore, survival was significantly worse in patients with a performance status (PS) of ≥2 compared to those with a PS of ≤1 and neurological complications occurred statistically more often in the group with worse PS (≥2). Survival rates were significantly lower in the non-spinal compared to those in the spinal metastatic group. Since the majority of breast cancer patients presented with metastasis in the spine, a breast cancer origin was a positive prognostic factor in patients with spinal metastases. Although there were no significant differences between computed tomography (CT) and 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)-CT in detecting primary lesions, CT may be the first choice due to its feasibility. In conclusion, lung cancer, SREs and worse PS were adverse prognostic factors for patients with bone metastasis. In addition, CT scans may be more useful for determining the primary lesion of a bone metastasis compared to 18F-FDG PET-CT in a timelier manner.

Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation.

The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma.

RBPJ is a novel target for rhabdomyosarcoma therapy.

The Notch pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal development. In addition, the Notch pathway plays an important role in controlling tumorigenesis. However, the role of RBPJ, a transcription factor in the Notch pathway, in the development of tumors is largely unknown. In this study, we focused on the role of RBPJ in the pathogenesis of rhabdomyosarcoma (RMS). Our data showed that Notch pathway genes were upregulated and activated in human RMS cell lines and patient samples. Inhibition of the Notch pathway by a γ-secretase inhibitor (GSI) decreased the in vitro proliferation of RMS cells. Knockdown of RBPJ expression by RNAi inhibited the anchorage-independent growth of RMS cells and the growth of xenografts in vivo. Additionally, overexpression of RBPJ promoted the anchorage-independent growth of RMS cells. Further, we revealed that RBPJ regulated the cell cycle in RMS xenograft tumors and decreased proliferation. Our findings suggest that RBPJ regulates the RMS growth, and that the inhibition of RBPJ may be an effective therapeutic approach for patients with RMS.

Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells.

Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI.

Dropped head syndrome due to myogenic atrophy - a case report of surgical treatment.

We report a case of a 69-year-old man with dropped head syndrome associated with isolated neck extensor myopathy (INEM). Over a period of 2 years, he exhibited progressive inability to lift his chin off his chest, resulting in the dropped head position that impaired his activities of daily living. He had a disturbed gait with severe imbalance of spinal alignment. Computed tomography revealed osseous contracture of cervical vertebral bodies in flexed position. Anterior combined posterior reconstruction surgery yielded a successful outcome in his activities of daily living, including his walking balance of spinal alignment. Pathologic study confirmed myogenic atrophy in the cervical extensor muscles. We suggest that consideration for surgical management should be given to dropped head syndrome especially due to INEM.

Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury.

The body's capacity to restore damaged neural networks in the injured CNS is severely limited. Although various treatment regimens can partially alleviate spinal cord injury (SCI), the mechanisms responsible for symptomatic improvement remain elusive. Here, using a mouse model of SCI, we have shown that transplantation of neural stem cells (NSCs) together with administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, dramatically enhanced the restoration of hind limb function. VPA treatment promoted the differentiation of transplanted NSCs into neurons rather than glial cells. Transsynaptic anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits, and electron microscopic analysis revealed that the transplant-derived neurons both received and sent synaptic connections to endogenous neurons. Ablation of the transplanted cells abolished the recovery of hind limb motor function, confirming that NSC transplantation directly contributed to restored motor function. These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI.

Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2.

Methyl-CpG-binding protein 2 (MeCP2), a methyl-CpG-binding domain protein family member which is expressed predominantly in neurons in the nervous system, acts as a transcriptional repressor by binding to methylated genes, and mutations in mecp2 cause the neurological disorder known as Rett syndrome (RTT). Although MeCP2 has been reported to regulate neuronal maturation rather than fate specification of neural precursor cells (NPCs), we have previously shown that it inhibits astrocyte differentiation of NPCs when ectopically expressed. Here, we show that expression of MeCP2 in NPCs not only suppresses astrocytic differentiation but actually promotes neuronal differentiation, even in the presence of well-known astrocyte-inducing cytokines. This dual function of MeCP2 was abolished by the MEK inhibitor U0126. Moreover, we observed that a truncated form of MeCP2 found in RTT patients fails to promote neuronal differentiation. We further demonstrate that transplanted MeCP2-expressing NPCs differentiate in vivo into neurons in two non-neurogenic regions, striatum and spinal cord. These results suggest a possible therapeutic application for MeCP2 in neurodegenerative diseases and injuries to the central nervous system.

Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells.

Astrocytes play important roles in brain development and injury response. Transcription factors STAT3 and Smad1, activated by leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2), respectively, form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells (NECs) (K. Nakashima, M. Yanagisawa, H. Arakawa, N. Kimura, T. Hisatsune, M. Kawabata, K. Miyazono, and T. Taga, Science 284:479-482, 1999). However, the mechanisms that govern astrogliogenesis during the determination of the fate of neural stem cells remain elusive. Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs. The BMP antagonist Noggin abrogated LIF-induced Smad1 activation and astrogliogenesis by inhibiting BMPs produced by NECs. NECs deficient in suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3, readily differentiated into astrocytes upon activation by LIF not only due to sustained activation of STAT3 but also because of the consequent activation of Smad1. Our study suggests a novel LIF-triggered positive regulatory loop that enhances astrogliogenesis.

Mechanisms of neural stem cell fate determination: extracellular cues and intracellular programs.

Multipotent neural stem cells (NSC) possess the ability to self-renew and to generate the three major central nervous system (CNS) cell types: neurons, astrocytes and oligodendrocytes. However, the molecular mechanisms that control NSC fate specification are not yet fully understood. Recent studies have provided evidence that soluble protein mediators such as cytokines and transcriptional factors play critical roles in cell fate determination. Furthermore, it has become apparent that epigenetic gene regulation plays an important intracellular role as cell-intrinsic programs in the specification of cell lineages. In this review, we focus on recent progress that addresses the mechanisms of NSC fate specification and their possible contribution in the field of regenerative medicine.