Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

doi:10.1016/j.neulet.2008.10.040

Neuroscience Letters

Volume 448, Issue 1, 19 December 2008, Pages 71-73

https://doi.org/10.1016/j.neulet.2008.10.040 Get rights and content

Abstract

Multiple sclerosis is a currently incurable inflammatory demyelinating syndrome. Recent reports suggest that bone marrow derived mesenchymal stem cells may have therapeutic potential in experimental models of demyelinating disease, but various alternative mechanisms, ranging from systemic immune effects to local cell replacement, have been proposed. Here we used intraperitoneal delivery of human mesenchymal stem cells to help test (a) whether human cells can indeed suppress disease, and (b) whether CNS infiltration is required for any beneficial effect. We found pronounced amelioration of clinical disease but profoundly little CNS infiltration. Our findings therefore help confirm the therapeutic potential of mesenchymal stem cells, show that this does indeed extend to human cells, and are consistent with a peripheral or systemic immune effect of human MSCs in this model.

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Intravenous transplantation of bone marrow-derived mesenchymal stromal cells in patients with multiple sclerosis, a phase I/IIa, double blind, randomized controlled study
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Multiple sclerosis (MS) is a progressive, demyelinating neurodegenerative disease of the central nervous system. MS is immune-mediated and leads to disability especially in young adults. Even though 18 MS therapy drugs were approved, they slightly inhibit disease progression and do not induce regeneration and repair in the nervous system. Mesenchymal stromal cells (MSCs) have emerged as a new therapeutic modality in regenerative medicine and tissue engineering due to their immunomodulation and bio regenerative properties. We have designed a randomized, controlled clinical trial to assess safety and possible efficacy of MSC application in MS patients. Twenty-one MS patients were enrolled. Patients were allocated in two distinct groups: treatment group, which received systemic transplantation of autologous bone marrow-derived MSCs, and control group, which received placebo at the first injections. Patients in control group received MSCs at the second injection while the treatment group received placebo. All the patients were followed for 18 months. Follow-ups included regular visits, laboratory evaluation, and imaging analysis. Control patients received MSCs six month after treatment group. No severe immediate or late adverse events were observed in both groups after interventions. We did not find any significant differences in the rate of relapses, Expanded Disability Status Scale (EDSS) score, cognitive condition, Magnetic Resonance Imaging (MRI) findings, or any biomarkers of cerebrospinal fluid between the two groups and in each group before and after cell infusion. Transplantation of autologous bone marrow-derived mesenchymal stromal cells is safe and feasible. The efficacy of transplantation of these cells should be evaluated through designing randomized clinical trials with larger sample sizes, different administration routes, other cell types (allogeneic adipose derived MSCs, allogeneic Wharton's jelly derived MSCs …), repeated injections, and longer follow-up periods.
New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders: Combining with intranasal delivery
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Citation Excerpt :
The flexible treatment regimens provided by the non-invasive IN route also could solve problems in invasiveness and regimen of stem cells or EVs-based therapy. As we discussed above, IN route showed many advantages over current used administration route: the IV route has a poor lesion site transplantation rate69‒71; the topical injection is highly invasive and the frequency of dosage in topical injection was constrained77,145,160; other administration routes like intra-arterial (IA) or intraperitoneal injection (IP) also fail to realize high CNS delivery efficiency, and both are relatively invasive161,162. On the contrary, IN route could provide a direct nose-to-brain delivery and a high brain graft rate for stem cells or EVs.
The clinical translation of stem cells and their extracellular vesicles (EVs)-based therapy for central nervous system (CNS) diseases is booming. Nevertheless, the insufficient CNS delivery and retention together with the invasiveness of current administration routes prevent stem cells or EVs from fully exerting their clinical therapeutic potential. Intranasal (IN) delivery is a possible strategy to solve problems as IN route could circumvent the brain‒blood barrier non-invasively and fit repeated dosage regimens. Herein, we gave an overview of studies and clinical trials involved with IN route and discussed the possibility of employing IN delivery to solve problems in stem cells or EVs-based therapy. We reviewed relevant researches that combining stem cells or EVs-based therapy with IN administration and analyzed benefits brought by IN route. Finally, we proposed possible suggestions to facilitate the development of IN delivery of stem cells or EVs.
Effects of mesenchymal stem cells transplantation on multiple sclerosis patients
2020, Neuropeptides
Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with symptoms such as neuroinflammation and axonal degeneration. Existing drugs help reduce inflammatory conditions and protect CNS from demyelination and axonal damage; however, these drugs are unable to enhance axonal repair and remyelination. In this regard, cell therapy is considered as a promising regenerative approach to MS treatment. High immunomodulatory capacity, neuro-differentiation and neuroprotection properties have made Mesenchymal Stem Cells (MSCs) particularly useful for regenerative medicine. There are scant studies on the role of MSCs in patients suffering from MS. The low number of MS patients and the lack of control groups in these studies may explain the lack of beneficial effects of MSC transplantation in cell therapies. In this review, we evaluated the beneficial effects of MSC transplantation in clinical studies in terms of immunomodulatory, remyelinating and neuroprotecting properties of MSCs.
Mesenchymal stem cells in experimental autoimmune encephalomyelitis model of multiple sclerosis: A systematic review and meta-analysis
2020, Multiple Sclerosis and Related Disorders
Mesenchymal stem cells (MSCs) transplantation has been considered a possible therapeutic method for Multiple Sclerosis (MS). However, no quantitative data synthesis of MSCs therapy for MS exists. We conducted a systematic review and meta-analysis to evaluate the effects of MSCs in experimental autoimmune encephalomyelitis (EAE) animal model of MS.
We identified eligible studies published from January 1980 to January 2017 by searching four electronic databases (PubMed, MEDLINE, Embase and Web of Science). The outcome was the effects of MSCs on clinical performance evaluated by the EAE clinical score.
36 preclinical studies including 675 animals in MSCs treatment group, and 693 animals in control group were included in this meta-analysis. We found that MSCs transplantation significantly ameliorated the symptoms and delayed the disease progression (SMD = -1.25, 95% CI: -1.45 to -1.05, P < 0.001). However, no significant differences in effect sizes were unveiled relative to clinical score standard (P = 0.35), type of MSCs (P = 0.35), source of MSCs (P = 0.06), MSCs dose (P = 0.44), delivery methods (P = 0.31) and follow up period (P = 0.73).
The current study showed that MSCs transplantation could ameliorate clinical performance in EAE animal model of MS. These findings support the further studies translate MSCs to treat MS in humans.
Modulation of host immune responses following non-hematopoietic stem cell transplantation: Translational implications in progressive multiple sclerosis
2019, Journal of Neuroimmunology
There exists an urgent need for effective treatments for those patients suffering from chronic/progressive multiple sclerosis (MS). Accordingly, it has become readily apparent that different classes of stem cell-based therapies must be explored at both the basic science and clinical levels. Herein, we provide an overview of the basic mechanisms underlying the pre-clinical benefits of exogenously delivered non-hematopoietic stem cells (nHSCs) in animal models of MS. Further, we highlight a number of early clinical trials in which nHSCs have been used to treat MS. Finally, we identify a series of challenges that must be met and ultimately overcome if such promising therapeutics are to be advanced from the bench to the bedside.
Stem Cells in Multiple Sclerosis
2016, Translational Neuroimmunology in Multiple Sclerosis: From Disease Mechanisms to Clinical Applications
To overcome the limited capacity of the central nervous system (CNS) for regeneration, the theoretical alternative would be to use stem cells for more effective management of chronic degenerative and inflammatory neurological conditions, such as multiple sclerosis (MS). The precise reasons for the progression of disability in MS, despite the increasingly effective immunomodulating therapies, also remain largely obscure and puzzling. Recent findings indicate that progressive disease may be caused by axonal damage and atrophy, but can be also related to compartmentalized inflammation, which is purely amendable to the treatments and may be mediated by humoral mechanisms and cortical and deep gray matter damage. It seems therefore that in order to affect the progressive phases of the disease, alternative neuroprotective modalities are needed and include stem cell cellular therapies.
Although the adult brain contains small numbers of stem cells in restricted areas, this intrinsic stem cell repertoire is small and does not measurably contribute to functional recovery. Embryonic cells carrying pluripotent and self-renewal properties represent the stem cell prototype, but there are additional somatic stem cells that may be harvested and expanded from various tissues during adult life. Stem cell transplantation is based on the assumption that such cells may have the potential to regenerate or support the survival of the existing, partially damaged cells. A great deal of positive data from numerous preclinical and a few pilot clinical studies support the possibility of induction of neurotrophic and neuroprotective effects by stem cell therapies in MS. The mode of administration of the stem cells (and especially the intrathecal route that brings the cells in higher proximity to extensive areas of the CNS and has been long advocated and applied by our group) also may be crucial for the response of MS patients. Long-term safety data are still missing along with substantial evidence of clinical efficacy.

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Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

Abstract

J. Neuroimmunol.

J. Neuroimmunol.

J. Neurol. Sci.

Trends Immunol.

J. Autoimmun.

Blood

Exp. Neurol.

Cytotherapy