Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?

Abstract

Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; immunomodulation; stem cell therapy.

Figure 1

Schematic representation of stem cell therapy approach. Stem cell therapy is based on two macro-areas: sources of stem cell and routes of administration. Different tissue sources of stem cells have been examined for cell replacement therapies in neurodegenerative diseases. The most promising sources are showed in figure, all of them are characterized by specific advantages and limitation based on their origin and differentiation capacity. To date, only few routes of administration were tested and compared for efficacy. However, it is known that different administration routes can influence migration, distribution, and the amount of transplanted cells in the target area. In addition, administration routes influence dosage of stem cells and timing of cell delivery. Illustrations used elements from Servier Medical Art (https://smart.servier.com/, accessed on 15 July 2021).

Figure 2

Schematic representation of Alzheimer Disease AD pathophysiology. This progressive neurodegenerative disorder is characterized by atrophy of brain regions, leading to a significant reduction in brain volume correlated to cognitive decline and memory deficits. The neuropathological hallmarks of AD are represented by extracellular senile plaques (the brown ring in the inlet), composed of amyloid-β (Aβ) peptide, followed by intracellular deposition of neurofibrillary tangles (NFTs) generated by hyperphosphorylated protein tau. In addition, glial (pink cells) and microglial (yellow cells) activation and subsequent inflammatory responses are thought to contribute to the neurodegenerative symptoms of AD. Adapted from “Alzheimer’s Brain (Disintegrating Microtubule)” by BioRender.com (2021). Retrieved from (https://app.biorender.com/biorender-templates/, accessed on 13 July 2021).

Figure 3

Schematic representation of Amyotrophic Lateral Sclerosis (ALS) pathophysiology. ALS is a progressive neurodegenerative disease, with a multifactorial etiology, characterized by motor neurons’ death in the motor cortex and in the spinal cord’s ventral horn. Furthermore, astrocytes are not able to support neuronal functions and impaired glutamate clearance leads to neuronal excitotoxicity, this, combined with the secretion of pro-inflammatory cytokines by predominant activated microglia, contributes to the development of motor neuron dysfunction. The ventral roots become thin with loss of large myelinated fibers in motor nerves leading to denervation atrophy in affected muscles. Illustrations used elements from Servier Medical Art (https://smart.servier.com/, 12 July 2021).

Figure 4

Schematic representation of Parkinson Disease (PD) pathophysiology. The main pathological hallmark of PD the progressive degeneration of striatal-projecting midbrain dopaminergic neurons of the ventral forebrain due to aggregation and accumulation of the protein α-synuclein (Lewy bodies), which cause mitochondrial disfunctions, endoplasmatic reticulum (ER) stress, and Golgi degradation. Illustrations used elements from Servier Medical Art (https://smart.servier.com/, 15 July 2021).

Figure 5

Schematic roadmap to guide successful clinical trials and maximize therapeutical potential of iPSC-based personalized cell replacement for patients with neurodegenerative diseases. Illustrations used elements from Servier Medical Art (https://smart.servier.com, 14 July 2021).