From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L1 expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.

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Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

Mucosal Immunology ◽

10.1038/s41385-021-00455-x ◽

2021 ◽

Author(s):

Alba Angelina ◽

Mario Pérez-Diego ◽

Jacobo López-Abente ◽

Beate Rückert ◽

Ivan Nombela ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Inflammatory Diseases ◽

Endocannabinoid System ◽

Mitochondrial Activity ◽

Immune Mediated ◽

Therapeutic Tools ◽

Tolerogenic Dcs

AbstractThe generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.

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Induced Hyperglycemia in Mice is Controlled Following the Microfluidic System- Assisted Transplantation of Stem Cells-derived Insulin-producing Cells Transduced with miRNA

10.21203/rs.3.rs-77365/v1 ◽

2020 ◽

Author(s):

Adele Soltani ◽

Masoud Soleimani ◽

Mohammad Adel Ghiass ◽

Seyed Ehsan Enderami ◽

Shahram Rabbani ◽

...

Keyword(s):

Stem Cells ◽

Blood Glucose ◽

Functional Condition ◽

Microfluidic System ◽

Diabetic Mice ◽

Differentiation Potential ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Insulin Producing Cells

Abstract BackgroundCell-based therapy is a promising approach for the treatment of type 1 diabetes mellitus. Identification of stem cells as progenitor stem cells with differentiation potential to Insulin-producing cells (IPCs) and their application is an emerging issue. Different strategies have been used to support the cell survival and their specific functions to control hyperglycemia condition. Novel technology systems using appropriate materials/fibres can improve the cell transplantation.MethodsIn the present study, glucose-sensitive insulin-producing cells (IPCs) were differentiated from adipose-derived stem cells (ADSCs) transduced with miR-375 and anti-miR-7 to enhance the functions of the cells. The survival rate of the cells was also improved by using a microfluidic system prior to in vivo transplantation of the IPCs. The contribution of miR-375 with the anti-miR-7 in mature IPCs derived from ADSCs resulted in gaining the function of the cells as judged by insulin productionResultsAfter adopting a stable functional condition of the IPCs, the cells were used for in vivo grafting to diabetic mice which resulted in a substantial drop (5-folds) in blood glucose during four weeks of grafting. The pattern of blood glucose levels in the mice receiving fiber entrapped IPCs was similar to that of non-diabetic mice and blood glucose declined in animals treated with fiber-entrapped-IPCs. Blood insulin was elevated (2-folds) in diabetic mice received transplant of fiber-entrapped-IPCs carrying miR-375 and anti-miR-7 after five weeks of transplantation when compared to the untreated diabetic mice. For the first time, this study showed that the two-component microfluidic system is useful for supporting the Collagen-Alginate fiber-entrapped IPCs and the miRNAs-based cell therapy.ConclusionsOverall data show that the IPCs encapsulation by the microfluidic system can support the cells in terms of morphology and biological function and their efficiency for controlling the hyperglycemia condition in diabetic mice.

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Faculty Opinions recommendation of Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1122821.580959 ◽

2008 ◽

Author(s):

Jin-Xiong She

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice

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Faculty Opinions recommendation of Acute stimulation generates Tim-3-expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732439267.793543523 ◽

2018 ◽

Author(s):

Larry Kane

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Effector Function ◽

T Helper ◽

Helper Type

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Neuropharmacological Screening of Chiral and Non-chiral Phthalimide- Containing Compounds in Mice: in vivo and in silico Experiments

Medicinal Chemistry ◽

10.2174/1573406414666180525082038 ◽

2019 ◽

Vol 15 (1) ◽

pp. 102-118 ◽

Cited By ~ 1

Author(s):

Carolina Campos-Rodríguez ◽

José G. Trujillo-Ferrara ◽

Ameyali Alvarez-Guerra ◽

Irán M. Cumbres Vargas ◽

Roberto I. Cuevas-Hernández ◽

...

Keyword(s):

Locomotor Activity ◽

In Silico ◽

Biological Properties ◽

Chiral Molecules ◽

Chiral Compounds ◽

Plus Maze ◽

In Silico Studies ◽

The Central Nervous System

Background: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. Objective: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. Method: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). Results: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. Conclusion: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.

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Differentiation of mesenchymal stem cells from humans and animals into insulin-producing cells: An overview in vitro induction forms

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666201229124429 ◽

2020 ◽

Vol 16 ◽

Author(s):

Bruna O. S. Câmara ◽

Bruno M. Bertassoli ◽

Natália M. Ocarino ◽

Rogéria Serakides

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Culture Medium ◽

Adipogenic Differentiation ◽

Medium Composition ◽

Cell Therapies ◽

Insulin Producing Cells ◽

Msc Differentiation

The use of stem cells in cell therapies has shown promising results in the treatment of several diseases, including diabetes mellitus, in both humans and animals. Mesenchymal stem cells (MSCs) can be isolated from various locations, including bone marrow, adipose tissues, synovia, muscles, dental pulp, umbilical cords, and the placenta. In vitro, by manipulating the composition of the culture medium or transfection, MSCs can differentiate into several cell lineages, including insulin-producing cells (IPCs). Unlike osteogenic, chondrogenic, and adipogenic differentiation, for which the culture medium and time are similar between studies, studies involving the induction of MSC differentiation in IPCs differ greatly. This divergence is usually evident in relation to the differentiation technique used, the composition of the culture medium, the cultivation time, which can vary from a few hours to several months, and the number of steps to complete differentiation. However, although there is no “gold standard” differentiation medium composition, most prominent studies mention the use of nicotinamide, exedin-4, ß-mercaptoethanol, fibroblast growth factor b (FGFb), and glucose in the culture medium to promote the differentiation of MSCs into IPCs. Therefore, the purpose of this review is to investigate the stages of MSC differentiation into IPCs both in vivo and in vitro, as well as address differentiation techniques and molecular actions and mechanisms by which some substances, such as nicotinamide, exedin-4, ßmercaptoethanol, FGFb, and glucose, participate in the differentiation process.

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