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1.
Stem Cell Res Ther ; 15(1): 151, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38783390

ABSTRACT

BACKGROUND: Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. METHODS: The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. RESULTS: Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and - 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and - 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. CONCLUSION: Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1 .


Subject(s)
Injections, Spinal , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Humans , Male , Female , Mesenchymal Stem Cell Transplantation/methods , Middle Aged , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Adult , Double-Blind Method , Neural Stem Cells/cytology , Neural Stem Cells/transplantation , Multiple Sclerosis, Chronic Progressive/therapy , Multiple Sclerosis, Chronic Progressive/pathology , Treatment Outcome
2.
PLoS One ; 18(8): e0290069, 2023.
Article in English | MEDLINE | ID: mdl-37566599

ABSTRACT

Mesenchymal stem cell-neural progenitors (MSC-NP) are a neural derivative of MSCs that are being investigated in clinical trials as an autologous intrathecal cell therapy to treat patients with secondary progressive (SP) or primary progressive (PP) multiple sclerosis (MS). MSC-NPs promote tissue repair through paracrine mechanisms, however which secreted factors mediate the therapeutic potential of MSC-NPs and how this cell population differs from MSCs remain poorly understood. The objective of this study was to define the transcriptional profile of MSCs and MSC-NPs from MS and non-MS donors to better characterize each cell population. MSCs derived from SPMS, PPMS, or non-MS bone marrow donors demonstrated minimal differential gene expression, despite differences in disease status. MSC-NPs from both MS and non-MS-donors exhibited significant differential gene expression compared to MSCs, with 2,156 and 1,467 genes upregulated and downregulated, respectively. Gene ontology analysis demonstrated pronounced downregulation of cell cycle genes in MSC-NPs compared to MSC consistent with reduced proliferation of MSC-NPs in vitro. In addition, MSC-NPs demonstrated significant enrichment of genes involved in cell signaling, cell communication, neuronal differentiation, chemotaxis, migration, and complement activation. These findings suggest that increased cell signaling and chemotactic capability of MSC-NPs may support their therapeutic potential in MS.


Subject(s)
Mesenchymal Stem Cells , Multiple Sclerosis , Humans , Multiple Sclerosis/genetics , Multiple Sclerosis/therapy , Multiple Sclerosis/metabolism , Signal Transduction , Cell Differentiation
3.
Regen Med ; 18(3): 259-273, 2023 03.
Article in English | MEDLINE | ID: mdl-36852422

ABSTRACT

Background: Mesenchymal stem cell-derived neural progenitor cell (MSC-NP) therapy is an experimental approach to treat multiple sclerosis. The influence of MSC-NPs on microglial activation was investigated. Methods: Microglia were stimulated in the presence of MSC-NP-conditioned media, and proinflammatory or proregenerative marker expression was assessed by quantitative PCR and ELISA. Results: Microglia stimulated in the presence of MSC-NP-conditioned media displayed reduced expression of proinflammatory markers including CCL2, increased expression of proregenerative markers and reduced phagocytic activity. The paracrine effects of MSC-NPs from multiple donors correlated with TGF-ß3 gene expression and was reversed by TGF-ß signaling inhibition. Conclusion: MSC-NPs promote beneficial microglial polarization through secreted factors. This study suggests that microglia are a potential therapeutic target of MSC-NP cell therapy.


Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and spinal cord that leads to neuronal damage and neurological disability. A novel cell therapy has been developed aiming to slow or reverse neurological disability in patients with MS. The treatment approach utilizes bone marrow cells called mesenchymal stem cell-derived neural progenitors (MSC-NPs) that are injected into the spinal fluid of the patient. Microglia are an innate immune cell in the brain known to contribute to MS disease progression. This study explores whether microglia might be a therapeutic target of MSC-NP therapy. We found that MSC-NPs inhibited the inflammatory activation of microglia and increased proregenerative markers in microglia. These effects were mediated by the factors secreted by MSC-NPs, possibly including a secreted protein called TGF-ß. Overall, this study highlights a potential therapeutic mechanism of MSC-NP therapy in MS.


Subject(s)
Mesenchymal Stem Cells , Neural Stem Cells , Microglia , Culture Media, Conditioned/pharmacology , Stem Cell Transplantation
4.
Int J Mol Sci ; 23(22)2022 Nov 13.
Article in English | MEDLINE | ID: mdl-36430490

ABSTRACT

Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis. Human cancer research in general requires refined models to bridge the gap between basic science research and meaningful clinical trials. Classic studies in cultured cancer cell lines and animal models such as mice and rats often present caveats when extended to humans due to inherent genetic and physiological differences. However, larger animal models such as pigs are emerging as more appropriate tools for translational research as they present more similarities with humans in terms of genetics, anatomical structures, organ sizes, and pathological manifestations of diseases like cancer. These similarities make porcine models well-suited for addressing long standing questions in cancer biology as well as in the arena of novel drug and therapeutic development against human cancers. With the emergent roles of Cu in human health and pathology, the pig presents an emerging and valuable model to further investigate the contributions of this metal to human cancers. The Oncopig Cancer Model is a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors. In this review, we briefly outline the relationship between Cu and cancer, and how the novel Oncopig Cancer Model may be used to provide a better understanding of the mechanisms and causal relationships between Cu and molecular targets involved in cancer.


Subject(s)
Copper , Neoplasms , Mice , Swine , Humans , Animals , Rats , Neoplasms/genetics , Translational Research, Biomedical
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