Abstract
Neurodegenerative diseases are characterized by chronic and progressive structural or functional loss of neurons. Limitations related to the animal models of these human diseases have impeded the development of effective drugs. This emphasizes the need to establish disease models using human-derived cells. The discovery of induced pluripotent stem cell (iPSC) technology has provided novel opportunities in disease modeling, drug development, screening, and the potential for “patient-matched” cellular therapies in neurodegenerative diseases. In this study, with the objective of establishing reliable tools to study neurodegenerative diseases, we reprogrammed human umbilical vein endothelial cells (HUVECs) into iPSCs (HiPSCs). Using a novel and direct approach, HiPSCs were differentiated into cells of central nervous system (CNS) lineage, including neuronal, astrocyte and glial cells, with high efficiency. HiPSCs expressed embryonic genes such as nanog, sox2 and Oct-3/4, and formed embryoid bodies that expressed markers of the 3 germ layers. Expression of endothelial-specific genes was not detected in HiPSCs at RNA or protein levels. HiPSC-derived neurons possess similar morphology but significantly longer neurites compared to primary human fetal neurons. These stem cell-derived neurons are susceptible to inflammatory cell-mediated neuronal injury. HiPSC-derived neurons express various amino acids that are important for normal function in the CNS. They have functional receptors for a variety of neurotransmitters such as glutamate and acetylcholine. HiPSC-derived astrocytes respond to ATP and acetylcholine by elevating cytosolic Ca2+ concentrations. In summary, this study presents a novel technique to generate differentiated and functional HiPSC-derived neurons and astrocytes. These cells are appropriate tools for studying the development of the nervous system, the pathophysiology of various neurodegenerative diseases and the development of potential drugs for their treatments.
Highlights
Neuronal loss is the hallmark of neurodegenerative diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s diseases
Since contamination of induced pluripotent stem cell (iPSC) with animal cells is a major limitation for potential therapeutic purposes, we aimed to generate iPSCs from human umbilical vein endothelial cells (HUVECs) independent of feeder layers
Using the protocol described in the Materials and Methods, HUVECs were transduced with lentiviral vectors expressing reprogramming transcription factors
Summary
Neuronal loss is the hallmark of neurodegenerative diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis, Parkinson’s-, Alzheimer’s-, and Huntington’s diseases. It is widely reported that genetic mutations and environmental factors contribute to the pathogenesis of these diseases [1,2,3]. The goal of developing effective therapies for these diseases has not yet been achieved. A major hindrance towards this goal is the lack of appropriate models. Limitations of animal models accurately mimicking human pathophysiology are confounding factors in the failures of many potential drugs [4]. This emphasizes the need for disease models that are based on human cells [5,6,7]
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