Olfactory Ensheathing Cell Neurorestorotherapy for Amyotrophic Lateral Sclerosis Patients: Benefits from Multiple Transplantations

Abstract

Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of protein-tyrosine kinases, is an important regulator of signal transduction for the activation of cell growth, differentiation, and development. We have previously reported that activation of Etk leads to apoptosis in MDA-MB-468 cells. The purpose of this study was to examine the role of Etk in neuronal injury induced by H(2)O(2) or ischemia. Using Western blot analysis and immunohistochemistry, we found that treatment with H(2)O(2) significantly enhanced phosphorylation of Etk and its downstream signaling molecule Stat1 in primary cortical neurons. Inhibiting Etk activity by LFM-A13 or knocking down Etk expression by a specific shRNA increased the survival of primary cortical neurons. Similarly, at 1 day after a 60-min middle cerebral artery occlusion (MCAo) in adult rats, both phosphorylated Etk and Stat1 were coexpressed with apoptotic markers in neurons in the penumbra. Pretreatment with LFM-A13 or an adenoviral vector encoding the kinase deletion mutant Etkk attenuated caspase-3 activity and infarct volume in ischemic brain. All together, our data suggest that Etk is activated after neuronal injury. Suppressing Etk activity protects against neurodegeneration in ischemic brain.

Rethinking on ethics and regulations in cell therapy as part of neurorestoratology

“…32 2) Sharma et al presented a clinical analysis comparing the survival of 37 patients who received intrathecal transplantation of adult autologous bone marrow mononuclear cells with controls who did not receive cellular transplantation; they had observed increased survival in the treatment group. There were improvements observed clinically in bulbar symptoms and in gross and fine motor 33 Huang et al and Chen et al [34][35][36] published three reports. 1) In a controlled pilot study involving 35 patients with probable or definite ALS, determined by the assessment of ALS-FRSr, the functional deterioration was significantly slower in the OEC-treated group than in the control group during the last 2 months (P,0.05).…”

Olfactory ensheathing cell transplantation for a patient with chronic sciatic nerve injury

“…17,18 Following OEC transplantation, patients with complete chronic SCI, amyotrophic lateral sclerosis, chronic stroke, cerebral palsy, multiple system atrophy, Alzheimer's disease, etc could benefit from the restoration of some neurological functions and their quality of life could be improved. [19][20][21][22][23][24][25] During the period of recovery after acute phase, Schwann cells play an important role in peripheral nerve axonal regeneration and remyelination through providing neurotrophic support, guiding axonal regeneration, and myelinating the regenerated axons. [5][6][7][8][9] However, in chronic phase, endogenous Schwann cells may lose their abilities because of cellular atrophy and can no longer perform the functions of supporting, guiding axon regeneration, and myelinating; at that time, OEC transplantation may replace Schwann cells to play those roles.…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…At 4 months, reporting by the patients or caregivers indicated a reduction in disease progression rates. In a larger study involving 507 patients receiving intraspinal and intracortical injections (with many undergoing multiple intracortical injections), short-and long-term outcomes were reported [85,86], reflecting a statistically significant increase in ALSFRS-R scores following the injections, but no improvement in pulmonary function tests. Notably, 7 Dutch patients with ALS who underwent the procedure in China were evaluated at their local institution and showed no improvement in symptoms [81].…”