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Mesenchymal Stem Cells in Neurological Disorder

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 8486

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Dr. Jerran Santos

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Guest Editor

Advanced Tissue Engineering and Stem Cell Biology Group, University of Technology Sydney, Sydney, Australia
Interests: stem cells; regenerative medicine; systems biology; next-generation genome sequencing; bacterial pathogenesis; secreted moonlighting proteins; cytokine and immuno-modulation; 3D molecular modelling; protein interaction network building
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Bruce Milthorpe

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Guest Editor

Faculty of Science, University of Technology Sydney, Sydney, Australia
Interests: bioceramics; biomaterials evaluation techniques; biological molecule adsorption to surfaces; tissue engineering, stem cells
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Mesenchymal stem cells (MSCs) were first discovered by Alexander Friedenstein in the 1970s and named by Arnold Caplan in the early 1990s. Initially, described as a population of stromal cells derived from bone marrow that was plastic-adherent. These cells were shown to be self-renewing with debated multipotent or pluripotent differentiation capacity which has been the subject of many research endeavours. These cells are now known to be derived from a plethora of other adult tissues and have been shown to differentiate into a wide variety of adult cells and tissues. MSCs have been extensively utilised in clinical trials in autologous, allogenic, regenerative, and immunomodulatory applications. Conversely, there are only a few clinically approved therapies involving MSCs. These cells have bounds of potential in research and clinical translation, particularly in neurological disorders. Research deconvoluting neurological disorders’ complexities are paramount for expanding clinical translational applications. This special edition, therefore, shines the light on MSC research involved in neurological disorders.

Dr. Jerran Santos
Prof. Dr. Bruce Milthorpe
Guest Editors

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Keywords

stem cells
neurological disorders
stroke
traumatic brain and spine injury
neurodevelopmental disorders
neurodegenerative disorders
molecular biology
translation
regenerative

Published Papers (6 papers)

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Research

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23 pages, 4207 KiB

Open AccessArticle

Development of Good Manufacturing Practice-Compatible Isolation and Culture Methods for Human Olfactory Mucosa-Derived Mesenchymal Stromal Cells

by Christopher J. Kelly, Susan L. Lindsay, Rebecca Sherrard Smith, Siew Keh, Kyle T. Cunningham, Katja Thümmler, Rick M. Maizels, John D. M. Campbell and Susan C. Barnett

Int. J. Mol. Sci. 2024, 25(2), 743; https://doi.org/10.3390/ijms25020743 - 6 Jan 2024

Viewed by 943

Abstract

Demyelination in the central nervous system (CNS) resulting from injury or disease can cause loss of nerve function and paralysis. Cell therapies intended to promote remyelination of axons are a promising avenue of treatment, with mesenchymal stromal cells (MSCs) a prominent candidate. We have previously demonstrated that MSCs derived from human olfactory mucosa (hOM-MSCs) promote myelination to a greater extent than bone marrow-derived MSCs (hBM-MSCs). However, hOM-MSCs were developed using methods and materials that were not good manufacturing practice (GMP)-compliant. Before considering these cells for clinical use, it is necessary to develop a method for their isolation and expansion that is readily adaptable to a GMP-compliant environment. We demonstrate here that hOM-MSCs can be derived without enzymatic tissue digestion or cell sorting and without culture antibiotics. They grow readily in GMP-compliant media and express typical MSC surface markers. They robustly produce CXCL12 (a key secretory factor in promoting myelination) and are pro-myelinating in in vitro rodent CNS cultures. GMP-compliant hOM-MSCs are comparable in this respect to those grown in non-GMP conditions. However, when assessed in an in vivo model of demyelinating disease (experimental autoimmune encephalitis, EAE), they do not significantly improve disease scores compared with controls, indicating further pre-clinical evaluation is necessary before their advancement to clinical trials. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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22 pages, 6719 KiB

Open AccessArticle

Neural Marker Expression in Adipose-Derived Stem Cells Grown in PEG-Based 3D Matrix Is Enhanced in the Presence of B27 and CultureOne Supplements

by Neus Gomila Pelegri, Aleksandra M. Stanczak, Amy L. Bottomley, Max L. Cummins, Bruce K. Milthorpe, Catherine A. Gorrie, Matthew P. Padula and Jerran Santos

Int. J. Mol. Sci. 2023, 24(22), 16269; https://doi.org/10.3390/ijms242216269 - 13 Nov 2023

Cited by 1 | Viewed by 1128

Abstract

Adipose-derived stem cells (ADSCs) have incredible potential as an avenue to better understand and treat neurological disorders. While they have been successfully differentiated into neural stem cells and neurons, most such protocols involve 2D environments, which are not representative of in vivo physiology. In this study, human ADSCs were cultured in 1.1 kPa polyethylene-glycol 3D hydrogels for 10 days with B27, CultureOne (C1), and N2 neural supplements to examine the neural differentiation potential of ADSCs using both chemical and mechanical cues. Following treatment, cell viability, proliferation, morphology, and proteome changes were assessed. Results showed that cell viability was maintained during treatments, and while cells continued to proliferate over time, proliferation slowed down. Morphological changes between 3D untreated cells and treated cells were not observed. However, they were observed among 2D treatments, which exhibited cellular elongation and co-alignment. Proteome analysis showed changes consistent with early neural differentiation for B27 and C1 but not N2. No significant changes were detected using immunocytochemistry, potentially indicating a greater differentiation period was required. In conclusion, treatment of 3D-cultured ADSCs in PEG-based hydrogels with B27 and C1 further enhances neural marker expression, however, this was not observed using supplementation with N2. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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16 pages, 2317 KiB

Open AccessArticle

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology

by Victoria Sook Keng Tung, Fasil Mathews, Marina Boruk, Gabrielle Suppa, Robert Foronjy, Michele T. Pato, Carlos N. Pato, James A. Knowles and Oleg V. Evgrafov

Int. J. Mol. Sci. 2023, 24(20), 15339; https://doi.org/10.3390/ijms242015339 - 19 Oct 2023

Cited by 3 | Viewed by 866

Abstract

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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23 pages, 3032 KiB

Open AccessArticle

Adipose-Derived Stem Cells Spontaneously Express Neural Markers When Grown in a PEG-Based 3D Matrix

by Neus Gomila Pelegri, Aleksandra M. Stanczak, Amy L. Bottomley, Bruce K. Milthorpe, Catherine A. Gorrie, Matthew P. Padula and Jerran Santos

Int. J. Mol. Sci. 2023, 24(15), 12139; https://doi.org/10.3390/ijms241512139 - 28 Jul 2023

Cited by 2 | Viewed by 1532

Abstract

Neurological diseases are among the leading causes of disability and death worldwide and remain difficult to treat. Tissue engineering offers avenues to test potential treatments; however, the development of biologically accurate models of brain tissues remains challenging. Given their neurogenic potential and availability, adipose-derived stem cells (ADSCs) are of interest for creating neural models. While progress has been made in differentiating ADSCs into neural cells, their differentiation in 3D environments, which are more representative of the in vivo physiological conditions of the nervous system, is crucial. This can be achieved by modulating the 3D matrix composition and stiffness. Human ADSCs were cultured for 14 days in a 1.1 kPa polyethylene glycol-based 3D hydrogel matrix to assess effects on cell morphology, cell viability, proteome changes and spontaneous neural differentiation. Results showed that cells continued to proliferate over the 14-day period and presented a different morphology to 2D cultures, with the cells elongating and aligning with one another. The proteome analysis revealed 439 proteins changed in abundance by >1.5 fold. Cyclic nucleotide 3′-phosphodiesterase (CNPase) markers were identified using immunocytochemistry and confirmed with proteomics. Findings indicate that ADSCs spontaneously increase neural marker expression when grown in an environment with similar mechanical properties to the central nervous system. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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Review

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30 pages, 3460 KiB

Open AccessReview

Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier

by Pablo Vargas-Rodríguez, Alejandro Cuenca-Martagón, Julia Castillo-González, Ignacio Serrano-Martínez, Raúl M. Luque, Mario Delgado and Elena González-Rey

Int. J. Mol. Sci. 2023, 24(18), 14117; https://doi.org/10.3390/ijms241814117 - 14 Sep 2023

Viewed by 1475

Abstract

Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer’s disease, Parkinson’s disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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11 pages, 709 KiB

Open AccessReview

Micro-Fragmented Adipose Tissue as a Natural Scaffold for Targeted Drug Delivery in Brain Cancer

by Alex Salagean, Adela Nechifor-Boila, Nosherwan Bajwa, Ylenia Pastorello and Mark Slevin

Int. J. Mol. Sci. 2023, 24(14), 11530; https://doi.org/10.3390/ijms241411530 - 16 Jul 2023

Cited by 2 | Viewed by 1566

Abstract

Major limitations in the effective treatment of neurological cancer include systemic cytotoxicity of chemotherapy, inaccessibility, and inoperability. The capability to successfully target a drug to the tumor site(s) without incurring serious side effects—especially in the case of aggressive tumors, such as glioblastoma and neuroblastoma—would represent a significant breakthrough in therapy. Orthotopic systems, capable of storing and releasing proteins over a prolonged period at the site of a tumor, that utilize nanoparticles, liposomes, and hydrogels have been proposed. One candidate for drug delivery is Micro-Fragmented Adipose Tissue (MFAT). Easily obtained from the patient by abdominal subcutaneous liposuction (autologous), and with a high content of Mesenchymal Stem Cells (MSCs), mechanically derived nanofat is a natural tissue graft with a structural scaffold organization. It has a well-preserved stromal vascular fraction and a prolonged capacity to secrete anti-tumorigenic concentrations of pre-absorbed chemotherapeutics within extracellular vesicles. This review discusses current evidence supporting the potential of drug-modified MFAT for the treatment of neurological cancer with respect to recent preclinical and in vitro studies. Possible limitations and future perspectives are considered. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Neurological Disorder)

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