Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders

Abstract

Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; brain ischemic stroke; neurodegenerative diseases; neuropathic pain; stem cells; therapy.

Figure 1

Demonstrating the promising role and challenges of different types of stem cell therapy in treating Parkinson’s disease. iPSCs: induced pluripotent stem cells, hPSCs: human pluripotent stem cells, fVM: fetal ventral mesencephalic tissue, MSCs: mesenchymal stem cells.

Figure 2

Demonstrating the promising role and challenges of different types of stem cell therapy in treating Huntington’s disease. iNSC: induced neuronal stem cells, iPSCs: induced pluripotent stem cells, hPSCs: human pluripotent stem cells, NSCs: neuronal stem cells, MSNs: striatal medium spiny neurons.

Figure 3

Selection criteria for patients of MS to be treated with aHSCs for a better outcome. Based on the EBMT and previous reports, Patients with early active disease stages, younger than 45 years old, with disease course lesser than 10 years and low scores of EDSS and no comorbidities are found to have better outcome on transplantation of autologous stem cells. EDSS: Kurtzke’s Expanded Disability Status Scale, EBMT: European Group for Blood and Marrow Transplantation.

Figure 4

Proposed mechanisms for central NP alleviation via different types of stem cell therapy. Based on previous research, there are three main mechanisms for the antinociceptive effects of stem cell therapy. These mechanisms encompass the modulation of the glial cells (microglia and astrocytes) functions, weakening or reversal of central sensitization and reduction in autophagy, apoptosis and inflammatory markers in the spinal cord. Each of these main mechanisms are mediated via different ways according to the type of stem cells investigated. It is obvious that BMSCs act via different mechanisms to induce the analgesic effect. Additionally, conditioning of the BMSCs via IL-1β adds to these mechanisms. The ADSCs act mainly via depressing the astrocyte markers. Moreover, the transplantation of autologous ADSCs reduces the autophagy, apoptotic and inflammatory markers in the spinal cord. ADSCs: adipose-derived stem cells; aADSCs: autologous adipose-derived stem cells; BMSCs: bone-marrow-derived stem cells; CCL7: chemokine (C-C Motif) ligand 7; CREB: cAMP response element-binding protein; GFAP: autoimmune glial fibrillary acid protein; IL-1β BMSCs: IL-1β conditioned bone-marrow-derived stem cells; LC3-BII: autophagy marker light chain 3; MAPK: mitogen-activated protein kinase; NMDA: N-methyl-D-aspartate receptor; P2X4R: purinergic 2X4 receptor; TGF- β1: transforming growth factor beta 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Figure 5

Proposed mechanisms involved in peripheral NP alleviation by stem cell therapy. Based on previous research, it is clear that there are two main mechanisms by which the different types of stem cells counteract hyperalgesia. These mechanisms are regulation of the anti-inflammatory responses and neuroprotection and promotion of the regeneration of myelin sheath. BMSCs act via the two mechanisms through a variety of pathways that varied according to the methodologies of the previous research. The ADSCs seem to regulate the anti-inflammatory responses, whilst the hADSCs work through the neuroprotective mechanism. The hAFMSCs act mainly via neuroprotection [31,233,234]. ADSCs: adipose-derived stem cells; ATF3: activating transcription factor 3; BMSCs: bone marrow derived stem cells; CGRP: calcitonin gene-related peptide CREB: cAMP response element-binding protein; DRG: dorsal root ganglion; GDNF: glial-derived neurotrophic factor; hADSCs: human adipose derived stem cells; hAFMSCs: amniotic fluid-derived mesenchymal stem cells; IB4: isolectin B4; IL: interleukin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B-cell transcription factor; NGF: nerve growth factor; pERK½: phosphorylated extracellular-regulated kinase ½; PGP9.5: protein gene product 9.5; p-p38-MAPK protein MAPK: mitogen-activated protein kinase; S100-CBP: S100 calcium-binding protein; TNF: tumor necrosis factor; SCI: spinal cord injury.