stem cells

https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-00960-3

https://www.ncbi.nlm.nih.gov/pubmed/32517808?dopt=Abstract

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Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.

Acta Neuropathol Commun. 2020 Jun 09;8(1):84

Authors: Sullivan GM, Knutsen AK, Peruzzotti-Jametti L, Korotcov A, Bosomtwi A, Dardzinski BJ, Bernstock JD, Rizzi S, Edenhofer F, Pluchino S, Armstrong RC

Abstract

Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.

PMID: 32517808 [PubMed – in process]

https://www.mdpi.com/2077-0383/8/12/2102

https://www.ncbi.nlm.nih.gov/pubmed/31810187?dopt=Abstract

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Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis-A Phase I Study.

J Clin Med. 2019 Dec 02;8(12):

Authors: Iacobaeus E, Kadri N, Lefsihane K, Boberg E, Gavin C, Törnqvist Andrén A, Lilja A, Brundin L, Blanc KL

Abstract

Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1-2 × 106 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3+ Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects.

PMID: 31810187 [PubMed]

https://www.nature.com/articles/s41409-019-0684-0

https://www.ncbi.nlm.nih.gov/pubmed/31558790?dopt=Abstract

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Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE).

Bone Marrow Transplant. 2019 Sep 26;:

Authors: Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D, Greco R, Jessop H, Kazmi M, Kirgizov K, Labopin M, Mancardi G, Martin R, Moore J, Muraro PA, Rovira M, Sormani MP, Snowden JA, European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE)

Abstract

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.

PMID: 31558790 [PubMed – as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31632539?dopt=Abstract

Mesenchymal stromal cells attenuate multiple sclerosis via IDO-dependent increasing the suppressive proportion of CD5+ IL-10+ B cells.

Am J Transl Res. 2019;11(9):5673-5688

Authors: Li H, Deng Y, Liang J, Huang F, Qiu W, Zhang M, Long Y, Hu X, Lu Z, Liu W, Zheng SG

Abstract

Multiple sclerosis (MS), one of the autoimmune and inflammatory diseases, is a major cause of neurological disability worldwide. The existing clinical treatments are not curable, and better treatments are urgently needed. Mesenchymal stromal cells (MSCs) have shown promise for treating MS, but the favorable effects and mechanism of MSC therapy on MS are still not fully understood. In this study, we analyzed the phenotypic feature of peripheral blood mononuclear cells (PBMCs) in MS patients and found that the patients exhibited an increase in the frequency of B cells, but a markedly decrease in frequency of CD5+ and IL-10+ B cells compared to healthy controls. Infusion of MSCs exhibited a significant therapeutic effect on the experimental autoimmune encephalomyelitis (EAE) mice, infiltration of mononuclear cells and demyelination of the spinal cords were both reduced in CNS of the mice, the frequency of CD5+ IL-10+ B cells in the mice was significantly increased. Additionally, when PBMCs or B cells from MS patients were co-cultured with MSCs, the frequency of CD5+ IL-10+ B cells also increased, the proliferative and immunosuppressive capacity of CD5+ B cells were significantly enhanced while the apoptosis ratio of this cellular subset significantly decreased. Moreover, those effects could be eliminated while the indoleamine 2,3-dioxygenase (IDO) inhibitor, D/L-1MT, was added to the co-cultured cells. In summary, this study suggests that MSCs can control EAE via IDO pathway to promote the proportion and function of CD5+ IL-10+ B cells, providing a promise to treat patients with MS in the clinical setting.

PMID: 31632539 [PubMed]

https://www.ncbi.nlm.nih.gov/pubmed/31441732?dopt=Abstract

http://www.eurekaselect.com/174438/article

Human Pluripotent Stem Cells in Neurodegenerative Diseases: Potentials, Advances, and Limitations.

Curr Stem Cell Res Ther. 2019 Aug 23;:

Authors: Kolagar TA, Farzaneh M, Nikkar N, Anbiyaiee A, Heydari E, Khoshnam SE

Abstract

Neurodegenerative diseases are progressive and uncontrolled gradual loss of motor neurons function or death of neuron cells in the central nervous system (CNS) and the mechanisms underlying their progressive nature remain elusive. There is urgent need to investigate therapeutic strategies and novel treatments for neural regeneration in disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the development and identification of pluripotent stem cells enabling the acquisition of a large number of neural cells in order to improve cell recovery after neurodegenerative disorders. Pluripotent stem cells which consist of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their ability to indefinitely self-renew and the capacity to differentiate into different types of cells. The first human ESC lines were established from donated human embryos; while, because of a limited supply of donor embryos, human ESCs derivation remains ethically and politically controversial. Hence, hiPSCs-based therapies have been shown as an effective replacement for human ESCs without embryo destruction. Compared to the invasive methods for derivation of human ESCs, human iPSCs has opened possible to reprogram patient-specific cells by defined factors and with minimally invasive procedures. Human pluripotent stem cells are a good source for cell-based research, cell replacement therapies and disease modeling. To date, hundreds of human ESC and human iPSC lines have been generated with the aim of treating various neurodegenerative diseases. In this review, we have highlighted the recent potentials, advances, and limitations of human pluripotent stem cells for the treatment of neurodegenerative disorders.

PMID: 31441732 [PubMed – as supplied by publisher]

https://www.mdpi.com/2227-9059/7/2/26

https://www.ncbi.nlm.nih.gov/pubmed/30935074?dopt=Abstract

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Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives.

Biomedicines. 2019 Mar 30;7(2):

Authors: Cuascut FX, Hutton GJ

Abstract

Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.

PMID: 30935074 [PubMed]

https://www.sciencedirect.com/science/article/pii/S1084952118300661?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30922957?dopt=Abstract

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Mesenchymal Stem Cell Therapies in Brain Disease.

Semin Cell Dev Biol. 2019 Mar 25;:

Authors: Sherman LS, Romagano MP, Williams SF, Rameshwar P

Abstract

As treatments for diseases throughout the body progress, treatment for many brain diseases has been at a standstill due to difficulties in drug delivery. While new drugs are being discovered in vitro, these therapies are often hindered by inefficient tissue distribution and, more commonly, an inability to cross the blood brain barrier. Mesenchymal stem cells are thus being investigated as a delivery tool to directly target therapies to the brain to treat wide array of brain diseases. This review discusses the use of mesenchymal stem cells in hypoxic disease (Hypoxic Ischemic Encephalopathy), an inflammatory neurodegenerative disease (Multiple Sclerosis), and a malignant condition (glioma).

PMID: 30922957 [PubMed – as supplied by publisher]

https://www.frontiersin.org/articles/10.3389/fimmu.2019.00238/full

https://www.ncbi.nlm.nih.gov/pubmed/30842772?dopt=Abstract

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Potential Therapeutic Features of Human Amniotic Mesenchymal Stem Cells in Multiple Sclerosis: Immunomodulation, Inflammation Suppression, Angiogenesis Promotion, Oxidative Stress Inhibition, Neurogenesis Induction, MMPs Regulation, and Remyelination Stimulation.

Front Immunol. 2019;10:238

Authors: Abbasi-Kangevari M, Ghamari SH, Safaeinejad F, Bahrami S, Niknejad H

Abstract

Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system with unknown etiology. It is accompanied by demyelination of the nerves during immunological processes in the presence of oxidative stress, hypoxia, cerebral hypo-perfusion, and dysregulation in matrix metalloproteinases (MMPs). Human amniotic mesenchymal stem cells (hAMSCs) as pluripotent stem cells possess some conspicuous features which could be of therapeutic value in MS therapy. hAMSCs could mimic the cascade of signals and secrete factors needed for promoting formation of stable neovasculature and angiogenesis. hAMSCs also have immunomodulatory and immunosuppressive effects on inflammatory processes and reduce the activity of inflammatory cells, migration of microglia and inhibit recruitment of certain immune cells to injury sites. hAMSCs attenuate the oxidative stress supported by the increased level of antioxidant enzymes and the decreased level of lipid peroxidation products. Furthermore, hAMSCs enhance neuroprotection and neurogenesis in brain injuries by inhibition of inflammation and promotion of neurogenesis. hAMSCs could significantly increase the expression of neurotrophic factors, which prevents neurons from initiating programmed cell death and improves survival, development, and function of neurons. In addition, they induce differentiation of neural progenitor cells to neurons. hAMSCs could also inhibit MMPs dysregulation and consequently promote the survival of endothelial cells, angiogenesis and the stabilization of vascular networks. Considering the mentioned evidences, we hypothesized here that hAMSCs and their conditioned medium could be of therapeutic value in MS therapy due to their unique properties, including immunomodulation and inflammation suppression; angiogenesis promotion; oxidative stress inhibition; neurogenesis induction and neuroprotection; matrix metalloproteinases regulation; and remyelination stimulation.

PMID: 30842772 [PubMed – in process]

https://www.valueinhealthjournal.com/article/S1098-3015(18)33235-2/fulltext?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1098301518332352%3Fshowall%3Dtrue

https://www.ncbi.nlm.nih.gov/pubmed/30711072?dopt=Abstract

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Economic Evaluation of Stem Cell Therapies in Neurological Diseases: A Systematic Review.

Value Health. 2019 02;22(2):254-262

Authors: Nagpal A, Milte R, Kim SW, Hillier S, Hamilton-Bruce MA, Ratcliffe J, Koblar SA

Abstract

OBJECTIVES: To examine economic evaluation studies of stem cell therapies (SCTs) in neurological disorders and to provide an overview of the quality of the economic evidence available on this topic.

METHODS: The review examined studies that performed an economic evaluation of the use of stem cells in adult patients with neurological diseases and that were published in English during the period 2007 to 2017. Data analyzed and reported included study population, disease indication, main analytical approaches for the economic analysis and perspective, key assumptions made or tested in sensitivity analyses, cost outcomes, estimates of incremental cost effectiveness, and approaches to quantifying decision uncertainty.

RESULTS: A total of three studies reporting on the findings of the economic evaluation of the use of SCT in stroke, Parkinson disease, and secondary progressive multiple sclerosis, respectively, were identified. All three studies conducted a cost-utility analysis using decision-analytic models and reported an incremental cost per quality-adjusted life-years gained (incremental cost-effectiveness ratio) versus standard care. These studies reported meaningful cost savings in stroke, Parkinson disease, and secondary progressive multiple sclerosis in the base-case scenarios.

CONCLUSIONS: Despite significant progress in clinical research in the use of SCT in neurological diseases, economic evaluation of these therapies is still at a nascent stage. Given the early stage of research inputs (clinical and cost outcomes data) into the models per se, further research is urgently needed to enable meaningful assessment of the cost effectiveness of these advanced therapies and to ensure sustainable access for population groups most likely to benefit in clinical practice.

PMID: 30711072 [PubMed – indexed for MEDLINE]