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Cells
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Stem Cells and Degenerative Diseases
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Stem Cells and Degenerative Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (1 July 2019) | Viewed by 26485

Special Issue Editors

Prof. Dr. Alfredo Gorio

E-Mail Website
Guest Editor
Department of Health Sciences, Faculty of Medicine, University of Milan, Polo H. San Paolo, via A di Rudinì 8, 20142 Milan, Italy
Interests: development of new drug therapies; Parkinson's disease; stem cells; tuberous sclerosis; neuronal degeneration and regeneration; proliferation and differentiation of pulmonary cells
Special Issues, Collections and Topics in MDPI journals
Dr. Stephana Carelli

E-Mail Website
Guest Editor
1. Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy
2. Pediatric Research Center "Romeo ed Enrica Invernizzi", University of Milan, Milan, Italy
Interests: cell therapies for neurodegenerative disease (spinal cord injury, Parkinson’s disease); molecular mechanisms of neuronal degeneration and regeneration (epigenetic and non-coding RNA); organoids; 3D culture systems; neural stem cells; mesenchymal stem cells, neurodevelopmental disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleauges,

Neurodegenerative diseases are incurable and debilitating conditions that result in the progressive degeneration and/or death of neural cells. Examples of neurodegenerative diseases include spinal cord injuries, amyotrophic lateral sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s disease. Extensive research in the area of regenerative medicine is focused on the development of cells, tissues and organs to restore function through transplantation. Stem cells are presented as frontiers of regenerative medicine because of their indefinite self-renewal and potential to differentiate into other types of cells. Several strategies are currently being developed and include cell therapies derived from autologous primary cell isolates, cell therapies derived from established cell lines, cell therapies derived from a variety of stem cells, including bone marrow/mesenchymal stem cells, embryonic stem cells, iPSCs, as well as cells tissues and organs from genetically-modified animals. Moreover, recent advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells to develop 3D organoids and tissue structures. The potential for organoids to provide more dynamic and physiologically relevant models for developmental processes, drug toxicity screening, disease modeling, and personalized medicine has generated high interest in the scientific community.

The main aim of this Special Issue is to publish research and key advancements including stem cells and their usage in repair, regeneration and therapy.

Prof. Alfredo Gorio
Dr. Stefana Carelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • stem cells
  • cell therapy
  • regenerative medicine
  • neurodegenerative disease
  • 3D organoids
  • transplantation
  • regeneration
  • 3D organoids

Published Papers (5 papers)

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Research

20 pages, 5743 KiB  
Article
Intranasally Administered Exosomes from Umbilical Cord Stem Cells Have Preventive Neuroprotective Effects and Contribute to Functional Recovery after Perinatal Brain Injury
by Gierin Thomi, Marianne Joerger-Messerli, Valérie Haesler, Lukas Muri, Daniel Surbek and Andreina Schoeberlein
Cells 2019, 8(8), 855; https://doi.org/10.3390/cells8080855 - 08 Aug 2019
Cited by 80 | Viewed by 6260
Abstract
Perinatal brain injury (PBI) in preterm birth is associated with substantial injury and dysmaturation of white and gray matter, and can lead to severe neurodevelopmental deficits. Mesenchymal stromal cells (MSC) have been suggested to have neuroprotective effects in perinatal brain injury, in part [...] Read more.
Perinatal brain injury (PBI) in preterm birth is associated with substantial injury and dysmaturation of white and gray matter, and can lead to severe neurodevelopmental deficits. Mesenchymal stromal cells (MSC) have been suggested to have neuroprotective effects in perinatal brain injury, in part through the release of extracellular vesicles like exosomes. We aimed to evaluate the neuroprotective effects of intranasally administered MSC-derived exosomes and their potential to improve neurodevelopmental outcome after PBI. Exosomes were isolated from human Wharton’s jelly MSC supernatant using ultracentrifugation. Two days old Wistar rat pups were subjected to PBI by a combination of inflammation and hypoxia-ischemia. Exosomes were intranasally administered after the induction of inflammation and prior to ischemia, which was followed by hypoxia. Infrared-labeled exosomes were intranasally administered to track their distribution with a LI-COR scanner. Acute oligodendrocyte- and neuron-specific cell death was analyzed 24 h after injury in animals with or without MSC exosome application using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical counterstaining. Myelination, mature oligodendroglial and neuronal cell counts were assessed on postnatal day 11 using immunohistochemistry, Western blot or RT-PCR. Morris water maze assay was used to evaluate the effect of MSC exosomes on long-term neurodevelopmental outcome 4 weeks after injury. We found that intranasally administered exosomes reached the frontal part of the brain within 30 min after administration and distributed throughout the whole brain after 3 h. While PBI was not associated with oligodendrocyte-specific cell death, it induced significant neuron-specific cell death which was substantially reduced upon MSC exosome application prior to ischemia. MSC exosomes rescued normal myelination, mature oligodendroglial and neuronal cell counts which were impaired after PBI. Finally, the application of MSC exosomes significantly improved learning ability in animals with PBI. In conclusion, MSC exosomes represent a novel prevention strategy with substantial clinical potential as they can be administered intranasally, prevent gray and white matter alterations and improve long-term neurodevelopmental outcome after PBI. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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15 pages, 5874 KiB  
Article
Bioink Composition and Printing Parameters for 3D Modeling Neural Tissue
by Valentina Fantini, Matteo Bordoni, Franca Scocozza, Michele Conti, Eveljn Scarian, Stephana Carelli, Anna Maria Di Giulio, Stefania Marconi, Orietta Pansarasa, Ferdinando Auricchio and Cristina Cereda
Cells 2019, 8(8), 830; https://doi.org/10.3390/cells8080830 - 05 Aug 2019
Cited by 52 | Viewed by 6246
Abstract
Neurodegenerative diseases (NDs) are a broad class of pathologies characterized by the progressive loss of neurons in the central nervous system. The main problem in the study of NDs is the lack of an adequate realistic experimental model to study the pathogenic mechanisms. [...] Read more.
Neurodegenerative diseases (NDs) are a broad class of pathologies characterized by the progressive loss of neurons in the central nervous system. The main problem in the study of NDs is the lack of an adequate realistic experimental model to study the pathogenic mechanisms. Induced pluripotent stem cells (iPSCs) partially overcome the problem, with their capability to differentiate into almost every cell types; even so, these cells alone are not sufficient to unveil the mechanisms underlying NDs. 3D bioprinting allows to control the distribution of cells such as neurons, leading to the creation of a realistic in vitro model. In this work, we analyzed two biomaterials: sodium alginate and gelatin, and three different cell types: a neuroblastoma cell line (SH-SY5Y), iPSCs, and neural stem cells. All cells were encapsulated inside the bioink, printed and cultivated for at least seven days; they all presented good viability. We also evaluated the maintenance of the printed shape, opening the possibility to obtain a reliable in vitro neural tissue combining 3D bioprinting and iPSCs technology, optimizing the study of the degenerative processes that are still widely unknown. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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17 pages, 4746 KiB  
Article
Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells
by Yi-Ping Yang, Phan Nguyen Nhi Nguyen, Tai-Chi Lin, Aliaksandr A. Yarmishyn, Wun-Syuan Chen, De-Kuang Hwang, Guang-Yuh Chiou, Tzu-Wei Lin, Chian-Shiu Chien, Ching-Yao Tsai, Shih-Hwa Chiou, Shih-Jen Chen, Chi-Hsien Peng and Chih-Chien Hsu
Cells 2019, 8(6), 625; https://doi.org/10.3390/cells8060625 - 21 Jun 2019
Cited by 14 | Viewed by 4165
Abstract
The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise [...] Read more.
The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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24 pages, 6807 KiB  
Article
Neuroprotection, Recovery of Function and Endogenous Neurogenesis in Traumatic Spinal Cord Injury Following Transplantation of Activated Adipose Tissue
by Stephana Carelli, Toniella Giallongo, Federica Rey, Mattia Colli, Delfina Tosi, Gaetano Bulfamante, Anna Maria Di Giulio and Alfredo Gorio
Cells 2019, 8(4), 329; https://doi.org/10.3390/cells8040329 - 08 Apr 2019
Cited by 19 | Viewed by 4536
Abstract
Spinal cord injury (SCI) is a devastating disease, which leads to paralysis and is associated to substantially high costs for the individual and society. At present, no effective therapies are available. Here, the use of mechanically-activated lipoaspirate adipose tissue (MALS) in a murine [...] Read more.
Spinal cord injury (SCI) is a devastating disease, which leads to paralysis and is associated to substantially high costs for the individual and society. At present, no effective therapies are available. Here, the use of mechanically-activated lipoaspirate adipose tissue (MALS) in a murine experimental model of SCI is presented. Our results show that, following acute intraspinal MALS transplantation, there is an engraftment at injury site with the acute powerful inhibition of the posttraumatic inflammatory response, followed by a significant progressive improvement in recovery of function. This is accompanied by spinal cord tissue preservation at the lesion site with the promotion of endogenous neurogenesis as indicated by the significant increase of Nestin-positive cells in perilesional areas. Cells originated from MALS infiltrate profoundly the recipient cord, while the extra-dural fat transplant is gradually impoverished in stromal cells. Altogether, these novel results suggest the potential of MALS application in the promotion of recovery in SCI. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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13 pages, 2493 KiB  
Article
FM19G11-Loaded Gold Nanoparticles Enhance the Proliferation and Self-Renewal of Ependymal Stem Progenitor Cells Derived from ALS Mice
by Stefania Marcuzzo, Davide Isaia, Silvia Bonanno, Claudia Malacarne, Paola Cavalcante, Antonella Zacheo, Valentino Laquintana, Nunzio Denora, Barbara Sanavio, Elisa Salvati, Patrizia Andreozzi, Francesco Stellacci, Silke Krol, Maravillas Mellado-López, Renato Mantegazza, Victoria Moreno-Manzano and Pia Bernasconi
Cells 2019, 8(3), 279; https://doi.org/10.3390/cells8030279 - 23 Mar 2019
Cited by 24 | Viewed by 4635
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. In ALS mice, neurodegeneration is associated with the proliferative restorative attempts of ependymal stem progenitor cells (epSPCs) that normally lie in a quiescent in the spinal cord. Thus, modulation of the [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. In ALS mice, neurodegeneration is associated with the proliferative restorative attempts of ependymal stem progenitor cells (epSPCs) that normally lie in a quiescent in the spinal cord. Thus, modulation of the proliferation of epSPCs may represent a potential strategy to counteract neurodegeneration. Recent studies demonstrated that FM19G11, a hypoxia-inducible factor modulator, induces epSPC self-renewal and proliferation. The aim of the study was to investigate whether FM19G11-loaded gold nanoparticles (NPs) can affect self-renewal and proliferation processes in epSPCs isolated from G93A-SOD1 mice at disease onset. We discovered elevated levels of SOX2, OCT4, AKT1, and AKT3, key genes associated with pluripotency, self-renewal, and proliferation, in G93A-SOD1 epSPCs at the transcriptional and protein levels after treatment with FM19G11-loaded NPs. We also observed an increase in the levels of the mitochondrial uncoupling protein (UCP) gene in treated cells. FM19G11-loaded NPs treatment also affected the expression of the cell cycle-related microRNA (miR)-19a, along with its target gene PTEN, in G93A-SOD1 epSPCs. Overall our findings establish the significant impact of FM19G11-loaded NPs on the cellular pathways involved in self-renewal and proliferation in G93A-SOD1 epSPCs, thus providing an impetus to the design of novel tailored approaches to delay ALS disease progression. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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