iPSC for modeling neurodegenerative disorders

Abstract

Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and new techniques to address these disorders, are being actively studied by researchers and medical personnel. In the present review we will discuss the application of induced Pluripotent Stem Cells (iPSCs) for cell-therapy replacement and disease modelling. The aim of iPSCs is to restore the functionality of the damaged tissue by replacing the impaired cells with competitive ones. To achieve this objective, iPSCs can be properly differentiated into virtually any cell fate and can be strongly translated into human health via in vitro and in vivo disease modeling for the development of new therapies, the discovery of biomarkers for several disorders, the elaboration and testing of new drugs as novel treatments, and as a tool for personalized medicine.

Keywords: AD, Alzheimer's disease; AFP, Alpha-Fetoprotein; Alzheimer; Aβ, β-Amyloid; B-III-TUB, β–III–Tubulin; BBB, Blood Brain Barrier; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; DOPAL, 3,4-Dihydroxyphenylacetaldehyde; EBs, Embryoid Bodies; FLASH, Fast Length Adjustment of Short Reads; LUHMES, Lund Human Mesencephalic Cell Line; MHC, Mayor Histocompatibility Complex; Neurodegenerative diseasaes; PCR, Polymerase Chain Reaction; PD, Parkinson's Disease; Parkinson; ROS, Reactive Oxygen Species; SCs, Stem Cells; SMA, Smooth-Muscle Antibody; SNPc, Substantia Nigra Pars Compacta; TH, Tyrosine Hydroxylase; WGS, Whole Genome Sequencing; gRNA, guide RNA; hESC, Human Embryonic Stem Cells; iPSCs; iPSCs, Induced Pluripotent Stem Cells; nsSNVs, nonsynonymous single nucleotide variants; pTau, Phosphorylated Tau.

Fig. 1

Induced Pluripotent Stem Cells and Embryonic Stem Cells characteristics comparision. Table indicating the differences between iPSCs and ESCs, regarding their source(s), their advantages and disadvantages significant for their use as disease models and potential cell treatments.

Fig. 2

A graphic of human iPSCs-based therapy. Somatic cells are collected from affected patients and cultured, then the somatic cells are reprogrammed into iPSCs. Additionally, with genome editing technology or a viral transduction method it is possible to genetically correct the patient-derived iPSCs. The corrected iPSCs are differentiated into specific cell types to match genetically healthy cells, available for their application for research and disease modelling or clinical treatments by transplanting into patients for cell therapy. Graphic adapted from (Shi et al., 2017). Created with BioRender.

Fig. 3

Cellular neurodegenerative process. The neurodegeneration process is initiated by metabolic disruption events in the neurons, such as protein overexpression or misfolding. These events activate microglial cells and the Blood Brain Barrier (BBB), sending signals (cytokines) which induce inflammation in the brain. Inflammation leads to neuronal damage and finally neurodegeneration. Created with BioRender.

Fig. 4

Parkinson's Disease model. In a model of PD, iPSCs might be genetically corrected or produced when the disorder is associated with a genetic aberration in order to generate neural progenitor cells and dopaminergic neurons by a differentiation protocol. These cells can be used for different purposes such as cryopreservation for further use, drug testing, scaling up and rodent/animal grafting for disease modelling and research. Created with BioRender.

Fig. 5

Alzheimer's Disease model. Differentiation of somatic cells from patients can be reprogrammed to iPSCs and then differentiated into several brain cell types for 3D in vitro AD modeling, to examine interactions between the different cell types. Created with BioRender.