A Narrative Review of Advances in Neural Precursor Cell Transplantation Therapies for Spinal Cord Injury

A spinal cord injury (SCI) is a destructive event that causes a permanent deficit in neurological function because of poor regenerative potential. Transplantation therapies have attracted attention for restoration of the injured spinal cord, and transplantation of neural precursor cells (NPCs) has been studied worldwide. Several groups have demonstrated functional recovery via this therapeutic intervention due to the multiple beneficial effects of NPC transplantation, such as reconstruction of neuronal circuits, remyelination of axons, and neuroprotection by trophic factors. Our group developed a method to induce NPCs from human induced pluripotent stem cells (hiPSCs) and established a transplantation strategy for SCI. Functional improvement in SCI animals treated with hiPSC-NPCs was observed, and the safety of transplanting these cells was evaluated from multiple perspectives. With selection of a safe cell line and pretreatment of the cells to encourage maturation and differentiation, hiPSC-NPC transplantation therapy is now in the clinical phase of testing for subacute SCI. In addition, a research challenge will be to expand the efficacy of transplantation therapy for chronic SCI. More comprehensive strategies involving combination treatments are required to treat this problematic situation

The dual origin of the peripheral olfactory system: placode and neural crest

<p>Abstract</p> <p>Background</p> <p>The olfactory epithelium (OE) has a unique capacity for continuous neurogenesis, extending axons to the olfactory bulb with the assistance of olfactory ensheathing cells (OECs). The OE and OECs have been believed to develop solely from the olfactory placode, while the neural crest (NC) cells have been believed to contribute only the underlying structural elements of the olfactory system. In order to further elucidate the role of NC cells in olfactory development, we examined the olfactory system in the transgenic mice Wnt1-Cre/Floxed-EGFP and P0-Cre/Floxed-EGFP, in which migrating NC cells and its descendents permanently express GFP, and conducted transposon-mediated cell lineage tracing studies in chick embryos.</p> <p>Results</p> <p>Examination of these transgenic mice revealed GFP-positive cells in the OE, demonstrating that NC-derived cells give rise to OE cells with morphologic and antigenic properties identical to placode-derived cells. OECs were also positive for GFP, confirming their NC origin. Cell lineage tracing studies performed in chick embryos confirmed the migration of NC cells into the OE. Furthermore, spheres cultured from the dissociated cells of the olfactory mucosa demonstrated self-renewal and trilineage differentiation capacities (neurons, glial cells, and myofibroblasts), demonstrating the presence of NC progenitors in the olfactory mucosa.</p> <p>Conclusion</p> <p>Our data demonstrates that the NC plays a larger role in the development of the olfactory system than previously believed, and suggests that NC-derived cells may in part be responsible for the remarkable capacity of the OE for neurogenesis and regeneration.</p

Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero

Newly identified tissue-resident vascular precursor cells are recruited into growing vessels and contribute to vasculogenesis in adult mice

A Clinical Practice Guideline for the Management of Patients With Degenerative Cervical Myelopathy: Recommendations for Patients With Mild, Moderate, and Severe Disease and Nonmyelopathic Patients With Evidence of Cord Compression.

Study Design: Guideline development. Objectives: The objective of this study is to develop guidelines that outline how to best manage (1) patients with mild, moderate, and severe myelopathy and (2) nonmyelopathic patients with evidence of cord compression with or without clinical symptoms of radiculopathy. Methods: Five systematic reviews of the literature were conducted to synthesize evidence on disease natural history; risk factors of disease progression; the efficacy, effectiveness, and safety of nonoperative and surgical management; the impact of preoperative duration of symptoms and myelopathy severity on treatment outcomes; and the frequency, timing, and predictors of symptom development. A multidisciplinary guideline development group used this information, and their clinical expertise, to develop recommendations for the management of degenerative cervical myelopathy (DCM). Results: Our recommendations were as follows: (1) "We recommend surgical intervention for patients with moderate and severe DCM." (2) "We suggest offering surgical intervention or a supervised trial of structured rehabilitation for patients with mild DCM. If initial nonoperative management is pursued, we recommend operative intervention if there is neurological deterioration and suggest operative intervention if the patient fails to improve." (3) "We suggest not offering prophylactic surgery for non-myelopathic patients with evidence of cervical cord compression without signs or symptoms of radiculopathy. We suggest that these patients be counseled as to potential risks of progression, educated about relevant signs and symptoms of myelopathy, and be followed clinically." (4) "Non-myelopathic patients with cord compression and clinical evidence of radiculopathy with or without electrophysiological confirmation are at a higher risk of developing myelopathy and should be counselled about this risk. We suggest offering either surgical intervention or nonoperative treatment consisting of close serial follow-up or a supervised trial of structured rehabilitation. In the event of myelopathic development, the patient should be managed according to the recommendations above." Conclusions: These guidelines will promote standardization of care for patients with DCM, decrease the heterogeneity of management strategies and encourage clinicians to make evidence-informed decisions

A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on the use of methylprednisolone sodium succinate

Introduction: The objective of this guideline is to outline the appropriate use of methylprednisolone sodium succinate (MPSS) in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MPSS in acute SCI. A multidisciplinary Guideline Development Group used this information, in combination with their clinical expertise, to develop recommendations for the use of MPSS. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: The main conclusions from the systematic review included the following: (1) there were no differences in motor score change at any time point in patients treated with MPSS compared to those not receiving steroids; (2) when MPSS was administered within 8 hours of injury, pooled results at 6- and 12-months indicated modest improvements in mean motor scores in the MPSS group compared with the control group; and (3) there was no statistical difference between treatment groups in the risk of complications. Our recommendations were: (1) "We suggest not offering a 24-hour infusion of high-dose MPSS to adult patients who present after 8 hours with acute SCI"; (2) "We suggest a 24-hour infusion of high-dose MPSS be offered to adult patients within 8 hours of acute SCI as a treatment option"; and (3) "We suggest not offering a 48-hour infusion of high-dose MPSS to adult patients with acute SCI." Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in SCI patients

A clinical practice guideline for the management of patients with acute spinal cord injury and central cord syndrome: recommendations on the timing (<= 24 hours versus > 24 hours) of decompressive surgery

Objective: To develop recommendations on the timing of surgical decompression in patients with traumatic spinal cord injury (SCI) and central cord syndrome. Methods: A systematic review of the literature was conducted to address key relevant questions. A multidisciplinary guideline development group used this information, along with their clinical expertise, to develop recommendations for the timing of surgical decompression in patients with SCI and central cord syndrome. Based on GRADE, a strong recommendation is worded as "we recommend," whereas a weak recommendation is presented as "we suggest." Results: Conclusions from the systematic review included (1) isolated studies reported statistically significant and clinically important improvements following early decompression at 6 months and following discharge from inpatient rehabilitation; (2) in one study on acute central cord syndrome without instability, a marginally significant improvement in total motor scores was reported at 6 and 12 months in patients managed with early versus late surgery; and (3) there were no significant differences in length of acute care/rehabilitation stay or in rates of complications between treatment groups. Our recommendations were: "We suggest that early surgery be considered as a treatment option in adult patients with traumatic central cord syndrome" and "We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level." Quality of evidence for both recommendations was considered low. Conclusions: These guidelines should be implemented into clinical practice to improve outcomes in patients with acute SCI and central cord syndrome by promoting standardization of care, decreasing the heterogeneity of management strategies, and encouraging clinicians to make evidence-informed decisions

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Anticoagulant Thromboprophylaxis.

Introduction: The objective of this study is to develop evidence-based guidelines that recommend effective, safe and cost-effective thromboprophylaxis strategies in patients with spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions relating to thromboprophylaxis in SCI. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: Based on conclusions from the systematic review and expert panel opinion, the following recommendations were developed: (1) "We suggest that anticoagulant thromboprophylaxis be offered routinely to reduce the risk of thromboembolic events in the acute period after SCI;" (2) "We suggest that anticoagulant thromboprophylaxis, consisting of either subcutaneous low-molecular-weight heparin or fixed, low-dose unfractionated heparin (UFH) be offered to reduce the risk of thromboembolic events in the acute period after SCI. Given the potential for increased bleeding events with the use of adjusted-dose UFH, we suggest against this option;" (3) "We suggest commencing anticoagulant thromboprophylaxis within the first 72 hours after injury, if possible, in order to minimize the risk of venous thromboembolic complications during the period of acute hospitalization." Conclusions: These guidelines should be implemented into clinical practice in patients with SCI to promote standardization of care, decrease heterogeneity of management strategies and encourage clinicians to make evidence-informed decisions

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role of Baseline Magnetic Resonance Imaging in Clinical Decision Making and Outcome Prediction

Introduction: The objective of this guideline is to outline the role of magnetic resonance imaging (MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MRI in patients with traumatic SCI. This review focused on longitudinal studies that controlled for baseline neurologic status. A multidisciplinary Guideline Development Group (GDG) used this information, their clinical expertise, and patient input to develop recommendations on the use of MRI for SCI patients. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as “we recommend,” whereas a weaker recommendation is indicated by “we suggest.” Results: Based on the limited available evidence and the clinical expertise of the GDG, our recommendations were: (1) “We suggest that MRI be performed in adult patients with acute SCI prior to surgical intervention, when feasible, to facilitate improved clinical decision-making” (quality of evidence, very low) and (2) “We suggest that MRI should be performed in adult patients in the acute period following SCI, before or after surgical intervention, to improve prediction of neurologic outcome” (quality of evidence, low). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and prognostication for patients with SCI

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Rehabilitation.

Introduction: The objective of this study is to develop guidelines that outline the appropriate type and timing of rehabilitation in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to rehabilitation in patients with acute SCI. A multidisciplinary guideline development group used this information, and their clinical expertise, to develop recommendations for the type and timing of rehabilitation. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest. Results: Based on the findings from the systematic review, our recommendations were: (1) We suggest rehabilitation be offered to patients with acute spinal cord injury when they are medically stable and can tolerate required rehabilitation intensity (no included studies; expert opinion); (2) We suggest body weight-supported treadmill training as an option for ambulation training in addition to conventional overground walking, dependent on resource availability, context, and local expertise (low evidence); (3) We suggest that individuals with acute and subacute cervical SCI be offered functional electrical stimulation as an option to improve hand and upper extremity function (low evidence); and (4) Based on the absence of any clear benefit, we suggest not offering additional training in unsupported sitting beyond what is currently incorporated in standard rehabilitation (low evidence). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in patients with SCI by promoting standardization of care, decreasing the heterogeneity of management strategies and encouraging clinicians to make evidence-informed decisions