Abstract
Neurorestoratology is a promising discipline, which restores, promotes, and maintains the integrity of impaired or lost neuronal functions and/or structures, using novel cell-based comprehensive neurorestorative strategies. As we know, no matter what reasons cause the neural insults, they affect the neurons and glia or environment to present at physiological or different pathophysiological stages. Facing those insults, restoration by nature or intervention must occur through a wide variety of neurorestorative mechanisms. The entire attack or insults and restoration mechanisms should be generalized as a whole as the “neurorestorative process,” which refers to the entire changing process of the dynamic interaction between neural insults and restorative mechanisms. This International Association of Neurorestoratology (IANR) special issue of Cell Transplantation focuses on new explorations of the neurorestorative process, including positive clinical studies and interesting preclinical evidence further supporting the “CNS neurorestorable theory.”
Spinal Cord Injury
Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have benefited and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The review by Huang et al. (31 researchers from 20 countries) shows the increasing stronger evidence of clinical neurorestoration. This consensus tells the community and complete chronic spinal cord injury (SCI) patients that it is no longer right to say, “nothing can be done.”
Saberi et al. performed a Phase I/II clinical study of granulocyte-colony-stimulating factor (G-CSF) subcutaneous administration of 5 μg/kg per day for 7 consecutive days in 52 motor-complete and 22 motor-incomplete SCI patients. Motor-incomplete patients had significantly more improvement in American Spinal Injury Association (ASIA) motor score compared to the motor-complete patients; also they had significant improvement in light touch and pinprick sensory scores.
Al-Zoubi and his coworkers described the long-term safety and efficacy of unmanipulated, autologous, purified stem cells in patients with chronic SCIs. Patients were mobilized with G-CSF, and the CliniMACS magnetic separation system was used to purify cells. The percentages of cluster of differentiation 34-positive (CD34+) and CD133+ stem cells increased from an average of 2.1% in the initial leukapheresis products up to 95%. Then the cells were transplanted in 19 complete SCI (ASIA-A) patients. The cells were injected into three sites: the subarachnoid spaces proximal and distal to the injury site and into the cyst in the cord in the thoracic segments. The results of a 5-year follow-up showed that this was well tolerated in all patients, and seven patients (37%) had segmental sensory improvement (ASIA-B) and two patients (10%) had motor improvement (ASIA-C).
So far, there is not enough data to understand the best clinical potential of olfactory ensheathing cells (OECs), Schwann cells (SCs), or their combined use for therapeutic strategies. The aim of the clinical trial by Chen et al. was to examine and compare the benefits of using OECs with or without SCs in chronic complete cervical SCI cases. A total of seven patients finished this prospective randomized double blind clinical trial. Of them, three patients received an OEC intraspinal transplantation, one underwent SC implantation, whereas one received a combination of OECs and SCs. The remaining two patients were controls. Six months posttransplantation, no severe complication developed. All patients who received OECs, SCs alone, and a combination of them showed functional improvement, with electrophysiological improvement, except for one patient. Owing to the limitations of this study, the long-term observation of a large sample size is warranted in further studies.
Liang et al. examined the possibility that neural stem cells (NSCs) may have neuroprotective activities for SCI. Human NSCs (hNSCs) were isolated from cortical tissue of spontaneous aborted human fetuses. Continuous administration of cells after the SCI resulted in extensive growth of the corticospinal tract (CST) in the cervical region. NSCs reduced the number of caspase 3-positive apoptotic profiles at 7 days and protected against loss of the neurons 6 weeks after injury. NSCs promoted locomotor recovery in adult rats.
Stroke and Ischemia
Moniche et al. described the granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinase 2 (MMP-2) serum levels in stroke patients after intraarterial (IA) bone marrow mononuclear cell (BM-MNC) delivery. They found that BM-MNCs seem to induce changes in the serum levels of GM-CSF, PDGF-BB, and MMP-2, even 3 months after transplantation in subacute middle cerebral artery (MCA) stroke patients, which could be associated with better functional outcomes.
Qiao et al. reported a 2-year follow-up outcome of cotransplantation with neural stem/precursor cells (NSPCs) and mesenchymal stromal cells (MSCs) in ischemic stroke patients. Eight patients were enrolled. The patients were treated according to one of the following protocols: the first was four intravenous (IV) injections of MSCs at 0.5 × 106/kg body weight; the second regime was one IV injection of MSCs at 0.5 × 106/kg weight followed by three injections of MSCs at 5 × 106 and NSPCs at 6 × 106 through the cerebellomedullary cistern. No tumorigenesis was found. The neurological functions, disability levels, and daily living abilities of the patients improved. The data support the combined transplantation of NSPCs and MSCs and that it serves as a safe and feasible method for treating stroke.
Du et al. reported on the role of bone marrow stem cells (BMSCs) delivered by intra-arterial (IA) and IV injection in a rat transient middle cerebral artery occlusion model (MCAO). The BMSCs delivered via the IA route promoted angiogenesis and improved functional recovery. No reduction in cerebral blood flow (CBF) or microstrokes was detected. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) showed that brain perfusion and metabolism was better via IA injection.
Ju et al. improved brain ischemia by implantation of a new biomaterial composite in the injured area of the brain of the mouse via local angiogenesis. This composite used a hyaluronic acid (HA)-based biodegradable hydrogel scaffold, mixed with poly(lactic-co-glycolic acid) (PLGA) microspheres containing vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), factors that stimulate angiogenesis. This new material was shown to have good compatibility, survival, and proliferation of human umbilical artery endothelial cells (HUAECs), and NSCs were seen. Behavioral improvement was also seen after transplantation.
Cerebral Palsy
Given the potent anti-inflammatory activity and high regenerative potential of M2 macrophages, Chernykh et al. reported their clinical results using autologous M2 macrophages in 21 children with severe cerebral palsy. Intradural injection of M2 cells (mean dose of 0.8 × 106/kg) was performed in the lumbar spinal area. There was no mortality, psychomotor worsening, exacerbation of seizures, and long-term comorbidities, including tumors, during a 5-year follow-up. Gross and fine motor function recovered, and an improvement of cognitive activity and reduction of seizure syndrome were also observed.
Autism Spectrum Disorders
The prevalence of children found to be affected by autism spectrum disorders (ASDs) is rapidly increasing, and around 2% of US school-aged children are now involved. Bradstreet et al. investigated the safety and efficacy of fetal stem cells (FSCs) for 45 ASD patients, which consisted of two doses of intravenously and subcutaneously transplanted cells. Observation 12 months after treatment showed no adverse events of significance, including transmitted infections or immunological complications. Their speech, sociability, sensory ability, and health have improved.
Multiple Sclerosis
Li et al. used human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) to treat 23 multiple sclerosis (MS) patients. IV infusion of hUC-MSCs was applied three times in 6 weeks. The symptoms of the treated patients improved compared with the controls. Inflammatory cytokines were assessed, and data showed that a shift from Th1 to Th2 immunity occurred in hUC-MSC-treated patients.
Other Avenues
The possible advantages of intranasal administration of cells in comparison with systemic or surgical transplantation can be ascribed to: (1) its noninvasiveness and, therefore, the possibility of using multiple applications while avoiding extensive immunological response; (2) its more targeted and efficacious delivery to the brain in comparison with IV and IA administration. Danielyan et al. studied this novel approach of intranasal delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in mouse models of Alzheimer's (AD) and Parkinson's disease (PD). Their data showed for the first time the successful delivery of cells to the brain in the transgenic PD and AD mouse models via intranasal administration.
Skuk and Tremblay tested the IA injection of β-galactosidase (β-gal)-labeled myoblasts in macaques. Cells were injected into one of the femoral arteries in seven monkeys. Most β-Gal+ cells were observed in the capillaries and arterioles of muscles and other tissues of the leg homolateral to the cell injection, and they fused with myofibers in regions in which there was a process of myofiber regeneration.
In addition to studying the novel paradigm of proteome-based cell therapy for tumors, Bryukhovetskiy et al. compared the proteome mapping of tumor stem cells and tissue-specific stem cells of humans. They performed bioinformation analysis of protein lysates of human neural (CD133+) progenitor and stem cells (NPSCs) isolated from the olfactory sheath of a nose, multipotent mesenchymal (CD29+, CD44+, CD73+, CD90+, CD34–) stromal cells (MMSCs) isolated from human bone marrow, and tumor (CD133+) stem cells (TSCs) isolated from the human U87 glioblastoma cell line. They identified 1,664 proteins in the examined lysates of stem cells (SCs), 1,052 (63.2%) of which are identical in NPSCs and TSCs, and 607 proteins (36.47%) are identical in MMSCs and TSCs. The gliomaspheres of U87 glioblastoma had 10 intracellular pathways of signal transduction (IPST) that were not modified by neoplastic process, but only two of them were accessible for regulatory action on gene candidates in TSC nucleus. Carcinogenesis-free membrane proteins, IPST, and genes expressing proteins of these pathways in U87 glioblastoma TSCs can be viewed as main targets for regulatory effect on TSCs.
In summary, it is viable to promote functional neurorestoration through various strategies either in isolation or in combination in the neurorestorative process. Moreover, the new perspectives offered by the neurorestorative progress can help researchers to easily understand the real value of what they are doing, where they stand, and to capture great changes in many viewpoints of neurosciences and related clinical disciplines.