Dataset Information

Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.

ABSTRACT: Mesenchymal stem cells (MSCs) are a promising therapy for immune-mediated and inflammatory disorders, because of their potent immunomodulatory properties. In this study, we investigated the use of fresh, autologous, adipose-derived MSCs (ASCs) for feline chronic gingivostomatitis (FCGS), a chronic, debilitating, idiopathic, oral mucosal inflammatory disease. Nine cats with refractory FCGS were enrolled in this pilot study. Each cat received 2 intravenous injections of 20 million autologous ASCs, 1 month apart. Oral biopsies were taken before and at 6 months after the first ASC injection. Blood immune cell subsets, serum protein, and cytokine levels were measured at 0, 1, 3, and 6 months after treatment to assess immunomodulatory effects. Seven of the 9 cats completed the study. Five cats responded to treatment by either complete clinical remission (n=3) or substantial clinical improvement (n=2). Two cats were nonresponders. Cats that responded to treatment also exhibited systemic immunomodulation demonstrated by decreased numbers of circulating CD8+ T cells, a normalization of the CD4/CD8 ratio, decreased neutrophil counts, and interferon-? and interleukin (IL)-1? concentration, and a temporary increase in serum IL-6 and tumor necrosis factor-? concentration. No clinical recurrence has occurred following complete clinical remission (follow-up of 6-24 months). In this study, cats with <15% cytotoxic CD8 T cells with low expression of CD8 (CD8lo) cells were 100% responsive to ASC therapy, whereas cats with >15% CD8lo cells were nonresponders. The relative absence of CD8lo cells may be a biomarker to predict response to ASC therapy, and may shed light on pathogenesis of FCGS and mechanisms by which ASCs decrease oral inflammation and affect T-cell phenotype.This study is the first to demonstrate the safety and efficacy of fresh, autologous, adipose-derived stem cell systemic therapy for a naturally occurring, chronic inflammatory disease in cats. The findings demonstrate that this therapy resulted in complete clinical and histological resolution or reduction in clinical disease severity and immune modulation in most cats. This study also identified a potentially useful biomarker that could dictate patient enrollment and shed light on immune modulation mechanism. As a naturally occurring animal model, FCGS also provides a strategic platform for potentially translatable therapy for the treatment of human oral inflammatory disease.

SUBMITTER: Arzi B

PROVIDER: S-EPMC4704876 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.

Arzi Boaz B Mills-Ko Emily E Verstraete Frank J M FJ Kol Amir A Walker Naomi J NJ Badgley Megan R MR Fazel Nasim N Murphy William J WJ Vapniarsky Natalia N Borjesson Dori L DL

Stem cells translational medicine 20151118 1

<h4>Unlabelled</h4>Mesenchymal stem cells (MSCs) are a promising therapy for immune-mediated and inflammatory disorders, because of their potent immunomodulatory properties. In this study, we investigated the use of fresh, autologous, adipose-derived MSCs (ASCs) for feline chronic gingivostomatitis (FCGS), a chronic, debilitating, idiopathic, oral mucosal inflammatory disease. Nine cats with refractory FCGS were enrolled in this pilot study. Each cat received 2 intravenous injections of 20 milli ...[more]

PMID: 26582907

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Project description:Background and aimsRefractory epilepsy is also known as drug-resistant epilepsy with limited clinical treatment. Benefitting from its safety and easy availability, olfactory mucosa mesenchymal stem cells (OM-MSCs) are considered a preferable MSC source for clinical application. This study aims to investigate whether OM-MSCs are a promising alternative source for treating refractory epilepsy clinically and uncover the mechanism by OM-MSCs administration on an epileptic mouse model.MethodsOM-MSCs were isolated from turbinal and characterized by flow cytometry. Autologous human OM-MSCs treatment on a patient was carried out using intrathecal administration. Epileptic mouse model was established by 1 mg/kg scopolamine and 300 mg/kg pilocarpine treatment (intraperitoneal). Stereotaxic microinjection was employed to deliver the mouse OM-MSCs. Mouse electroencephalograph recording was used to investigate the seizures. Brain structure was evaluated by magnetic resonance imaging (MRI). Immunohistochemical and immunofluorescent staining of GFAP, IBA1, MAP2, TUBB3, OLIG2, CD4, CD25, and FOXP3 was carried out to investigate the neural cells and Treg cells. QRT-PCR and ELISA were performed to determine the cytokines (Il1b, Il6, Tnf, Il10) on mRNA and protein level. Y-maze, the object location test, and novel object recognition test were performed to measure the cognitive function. Footprint test, rotarod test, balance beam test, and grip strength test were conducted to evaluate the locomotive function. Von Frey testing was carried out to assess the mechanical allodynia.ResultsMany beneficial effects of the OM-MSC treatment on disease status, including seizure type, frequency, severity, duration, and cognitive function, and no apparent adverse effects were observed at the 8-year follow-up case. Brain MRI indicated that autologous OM-MSC treatment alleviated brain atrophy in epilepsy patients. A study in an epileptic mouse model revealed that OM-MSC treatment recruited Treg cells to the brain, inhibited inflammation, rebuilt the neural network, and improved the cognitive, locomotive, and perceptive functions of epileptic mice.ConclusionsAutologous OM-MSC treatment is efficacious for improving chronic refractory epilepsy, suggesting a future therapeutic candidate for epilepsy.Trial registrationThe study was registered with Chinese Clinical Trial Registry (ChiCTR2200055357).

Project description:The feline calicivirus (FCV) causes infections in cats all over the world and seems to be related to a broad variety of clinical presentations, such as feline chronic gingivostomatitis (FCGS), a severe oral pathology in cats. Although its etiopathogeny is largely unknown, FCV infection is likely to be a main predisposing factor for developing this pathology. During recent years, new strategies for treating FCGS have been proposed, based on the use of mesenchymal stem cells (MSC) and their regenerative and immunomodulatory properties. The main mechanism of action of MSC seems to be paracrine, due to the secretion of many biomolecules with different biological functions (secretome). Currently, several pathologies in humans have been shown to be related to functional alterations of the patient's MSCs. However, the possible roles that altered MSCs might have in different diseases, including virus-mediated diseases, remain unknown. We have recently demonstrated that the exosomes produced by the adipose-tissue-derived MSCs (fAd-MSCs) from cats suffering from FCV-positive severe and refractory FCGS showed altered protein contents. Based on these findings, the goal of this work was to analyze the proteomic profile of the secretome produced by feline adipose-tissue-derived MSCs (fAd-MSCs) from FCV-positive patients with FCGS, in order to identify differences between them and to increase our knowledge of the etiopathogenesis of this disease. We used high-resolution mass spectrometry and functional enrichment analysis with Gene Ontology to compare the secretomes produced by the fAd-MSCs of healthy and calicivirus-positive FCGS cats. We found that the fAd-MSCs from cats with FCGS had an increased expression of pro-inflammatory cytokines and an altered proteomic profile compared to the secretome produced by cells from healthy cats. These findings help us gain insight on the roles of MSCs and their possible relation to FCGS, and may be useful for selecting specific biomarkers and for identifying new therapeutic targets.

Project description:Mimicking endochondral bone formation is a promising strategy for bone regeneration. To become a successful therapy, the cell source is a crucial translational aspect. Typically, autologous cells are used. The use of non-autologous mesenchymal stromal cells (MSCs) represents an interesting alternative. Nevertheless, non-autologous, differentiated MSCs may trigger an undesired immune response, hampering bone regeneration. The aim of this study was to unravel the influence of the immune response on endochondral bone regeneration, when using xenogeneic (human) or allogeneic (Dark Agouti) MSCs. To this end, chondrogenically differentiated MSCs embedded in a collagen carrier were implanted in critical size femoral defects of immunocompetent Brown Norway rats. Control groups were included with syngeneic/autologous (Brown Norway) MSCs or a cell-free carrier. The amount of neo-bone formation was proportional to the degree of host-donor relatedness, as no full bridging of the defect was observed in the xenogeneic group whereas 2/8 and 7/7 bridges occurred in the allogeneic and the syngeneic group, respectively. One week post-implantation, the xenogeneic grafts were invaded by pro-inflammatory macrophages, T lymphocytes, which persisted after 12 weeks, and anti-human antibodies were developed. The immune response toward the allogeneic graft was comparable to the one evoked by the syngeneic implants, aside from an increased production of alloantibodies, which might be responsible for the more heterogeneous bone formation. Our results demonstrate for the first time the feasibility of using non-autologous MSC-derived chondrocytes to elicit endochondral bone regeneration in vivo. Nevertheless, the pronounced immune response and the limited bone formation observed in the xenogeneic group undermine the clinical relevance of this group. On the contrary, although further research on how to achieve robust bone formation with allogeneic cells is needed, they may represent an alternative to autologous transplantation.

Dataset Information

Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.

Publications

Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.

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