Stem Cell Educator therapy in type 1 diabetes: From the bench to clinical trials

Zhao, Yong; Knight, Colette; Jiang, Zhaoshun; Delgado, Elías; Hoven, Anne Marie Van; Ghanny, Steven; Zhang, Zhou; Zhou, Huimin; Yu, Haibo; Hu, Wei; Li, Xia; Pérez-Basterrechea, Marcos; Zhao, Laura; Zhao, Yeqian; Giangola, Joseph; Weinberg, Rona Singer; Mazzone, Theodore

doi:10.1016/j.autrev.2022.103058

Cited by 9 publications

(7 citation statements)

References 74 publications

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“…found that the administration of Galectin-9 in vivo resulted in the selective loss of interferon-gamma-producing cells and the suppression of Th1 autoimmunity ( 42 ). Moreover, Galectin-9 is also shown to directly suppress activated B cells ( 43 , 44 ) and attenuate BCR activation and signaling ( 44 ). The results from the current study indicated that Galectin-9 was primarily originated from KCs (the M1 cluster), and IHC staining showed that Galectin-9 was significantly higher in the ALC group.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis

Zhang

Peng

et al. 2023

Front. Endocrinol.

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BackgroundAlcoholic and hepatitis B virus (HBV)-related liver cirrhosis has placed a tremendous burden on the healthcare system with limited treatment options. This study explored the differences in the immune status of alcoholic and HBV-related liver cirrhosis.MethodsA total of 15 human liver samples from the Third Xiangya Hospital of Central South University, including five healthy controls (HC group), five alcoholic cirrhosis patients (ALC group), and five HBV-related cirrhosis patients (HBV group) were used. Of these, eight samples, including 3 HC group, 2 ALC group and 3 HBV group, were randomly collected to do single-cell RNA sequencing (scRNA-seq). The degree of steatosis was assessed by H&E staining and the presence of intrahepatic immune cells was evaluated by immunochemistry (IHC).ResultsThe immune status of alcoholic and HBV-related liver cirrhosis differed significantly. ScRNA-seq analysis identified a higher ratio of intrahepatic monocyte/macrophages and an obvious decreased ratio of T cells and B cells in the ALC group than in the HBV group. IHC staining of intrahepatic monocyte/macrophages, T and B cell exhibited similar results with scRNA-seq analysis. CD5L+ Kupffer cells, a cell type involved in lipid metabolism, were the major monocyte/macrophage subset in ALC liver tissue. H&E staining indicated that the level of steatosis was more severe in the ALC than in the HBV group. Ligand/receptor analysis showed that the T cell exhaustion observed in the ALC liver may be related to the expression of Galectin-9 on Kupffer cells. Fewer B cells were also found in the ALC group and most had higher lipid metabolism, reduced ribosomal activity, and a dysregulated mitochondrial oxidative phosphorylation system. Moreover, scRNA-seq showed a significantly lower ratio of plasma B cells, indicating that the humoral immune response in the ALC liver was similarly dysfunctional. Ligand/receptor analysis also discovered that Galectin-9 expressed on Kupffer cells may inhibit humoral immunity.ConclusionPatients with ALC have different immune characteristics than those with HBV-induced cirrhosis, including an increased ratio of intrahepatic monocyte/macrophages and a dysfunctional adaptive immune response in the liver. Galectin-9 could serve as a potential therapeutic target for ALC treatment.

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis

Zhang

Peng

et al. 2023

Front. Endocrinol.

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“…During SCE therapy, a patient’s peripheral blood mononuclear cells (PBMCs) are collected and circulated through a cell separator, where they are co-cultured with adherent human CBSCs in vitro . The resulting “educated” cells, known as CBSC-treated PBMCs, are then reintroduced into the patient’s circulation ( 60 ). These “educated” immune cells can educate other immune cells after infusion, thereby reverse the root cause(s) of the autoimmune disease and resulting in the long-lasting clinical efficacy of Educator therapy.…”

Section: Exosomes Derived From Stem Cell and Their Effect On Immune/i...mentioning

confidence: 99%

“…Mechanistic studies revealed that the secretion of CBSC-derived exosomes (CBSC-EXOs) enabled polarization of human blood monocytes/macrophages into M2 macrophages, thereby fundamentally correcting self-immunity and inducing immune tolerance through various molecular and cellular mechanisms ( 60 ). CBSC-EXOs preferably and quickly bind to monocytes within 2-3 h. During the coculture of CBSCs with patient’s immune cells for clinical treatment during 8-9 h, the SCE-treated monocytes may transport the CBSC-EXOs back into the body, potentially leading to additional M2 differentiation and induction of tolerance ( 59 , 62 ).…”

Section: Exosomes Derived From Stem Cell and Their Effect On Immune/i...mentioning

confidence: 99%

The Immunomodulatory effect of exosomes in diabetes: a novel and attractive therapeutic tool in diabetes therapy

Li,

Hu,

et al. 2024

Front. Immunol.

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Exosomes carry proteins, metabolites, nucleic acids and lipids from their parent cell of origin. They are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Therefore, exosomes are often modified in reaction to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, all of which involve a significant inflammatory aspect. Here, we discuss how immune cell-derived exosomes origin from neutrophils, T lymphocytes, macrophages impact on the immune reprogramming of diabetes and the associated complications. Besides, exosomes derived from stem cells and their immunomodulatory properties and anti-inflammation effect in diabetes are also reviewed. Moreover, As an important addition to previous reviews, we describes promising directions involving engineered exosomes as well as current challenges of clinical applications in diabetic therapy. Further research on exosomes will explore their potential in translational medicine and provide new avenues for the development of effective clinical diagnostics and therapeutic strategies for immunoregulation of diabetes.

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“…Human cord blood-derived stem cells (CB-SCs) display a unique phenotype, with both embryonic and hematopoietic markers that distinguish them from other known types of stem cells, including hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). CB-SCs display the leukocyte common antigen CD45 and embryonic stem cell markers such as the transcription factor OCT 3/4 and SOX2, as well as the immune modulation-associated markers CD270 and CD274, but are negative for hematopoietic stem cell (HSC) marker CD34 and mesenchymal stem cell (MSC) markers CD90 and CD105 [1]. Our previous studies demonstrated that human CB-SCs display multiple immune modulations on T cells and monocytes/macrophages via surface molecules and released exosomes [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…CB-SCs display the leukocyte common antigen CD45 and embryonic stem cell markers such as the transcription factor OCT 3/4 and SOX2, as well as the immune modulation-associated markers CD270 and CD274, but are negative for hematopoietic stem cell (HSC) marker CD34 and mesenchymal stem cell (MSC) markers CD90 and CD105 [1]. Our previous studies demonstrated that human CB-SCs display multiple immune modulations on T cells and monocytes/macrophages via surface molecules and released exosomes [1,2]. Based on CB-SCs' immunomodulation, we developed the Stem Cell Educator®(SCE) therapy to treat immune dysfunction-associated diseases, including type 1 diabetes (T1D), type 2 diabetes (T2D), and alopecia areata (AA) [3][4][5], through international multicenter clinical trials in the United States, China, and Spain.…”

Section: Introductionmentioning

confidence: 99%

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

Hu,

Song,

et al. 2024

IJMS

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Background: We developed the Stem Cell Educator therapy among multiple clinical trials based on the immune modulations of multipotent cord blood-derived stem cells (CB-SCs) on different compartments of immune cells, such as T cells and monocytes/macrophages, in type 1 diabetes and other autoimmune diseases. However, the effects of CB-SCs on the B cells remained unclear. To better understand the molecular mechanisms underlying the immune education of CB-SCs, we explored the modulations of CB-SCs on human B cells. Methods: CB-SCs were isolated from human cord blood units and confirmed by flow cytometry with different markers for their purity. B cells were purified by using anti-CD19 immunomagnetic beads from human peripheral blood mononuclear cells (PBMCs). Next, the activated B cells were treated in the presence or absence of coculture with CB-SCs for 7 days before undergoing flow cytometry analysis of phenotypic changes with different markers. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized to evaluate the levels of galectin expressions on CB-SCs with or without treatment of activated B cells in order to find the key galectin that was contributing to the B-cell modulation. Results: Flow cytometry demonstrated that the proliferation of activated B cells was markedly suppressed in the presence of CB-SCs, leading to the downregulation of immunoglobulin production from the activated B cells. Phenotypic analysis revealed that treatment with CB-SCs increased the percentage of IgD+CD27− naïve B cells, but decreased the percentage of IgD−CD27+ switched B cells. The transwell assay showed that the immune suppression of CB-SCs on B cells was dependent on the galectin-9 molecule, as confirmed by the blocking experiment with the anti-galectin-9 monoclonal antibody. Mechanistic studies demonstrated that both calcium levels of cytoplasm and mitochondria were downregulated after the treatment with CB-SCs, causing the decline in mitochondrial membrane potential in the activated B cells. Western blot exhibited that the levels of phosphorylated Akt and Erk1/2 signaling proteins in the activated B cells were also markedly reduced in the presence of CB-SCs. Conclusions: CB-SCs displayed multiple immune modulations on B cells through the galectin-9-mediated mechanism and calcium flux/Akt/Erk1/2 signaling pathways. The data advance our current understanding of the molecular mechanisms underlying the Stem Cell Educator therapy to treat autoimmune diseases in clinics.

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Stem Cell Educator therapy in type 1 diabetes: From the bench to clinical trials

Cited by 9 publications

References 74 publications

Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis

Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis

The Immunomodulatory effect of exosomes in diabetes: a novel and attractive therapeutic tool in diabetes therapy

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

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