Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells

Rekittke, Nadine E.; Ang, Meidjie; Rawat, Divya; Khatri, Rahul; Linn, Thomas

doi:10.1155/2016/3764681

Cited by 25 publications

(16 citation statements)

References 205 publications

(240 reference statements)

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“…Although the high differentiation potential of embryonic stem cells and induced pluripotent stem cells surpasses that of MSCs, the latter have remained favorable for transplantation studies as MSCs are considered to be easily obtained from adult tissues, and exhibit immunodulatory and immunosuppressive properties, in addition to nontumorigenic differentiation potential ( 38 ). Therefore, MSCs have emerged as a better source for the generation of surrogate β cells ( 5 , 39 ). However, a number of studies have demonstrated that the hyperglycemic state in patients with diabetes may impair MSC function ( 40 , 41 ); the results of the present study indicated that cellular senescence may be one of the causes of this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

Zhang

Chen

et al. 2017

Molecular Medicine Reports

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It has previously been demonstrated that glucose is important in the process of stem cell aging. However, the mechanisms of cell senescence induced by high glucose (HG) remain to be elucidated. The preliminary study indicated that D-galactose induced mesenchymal stem cell (MSCs) aging. The present study demonstrated, following treatment with 11.0 or 22.0 mM HG for 14 days, that HG significantly promoted MSCs aging and the expression levels of phosphorylated (p-)phosphatidylinositol 3-kinase/protein kinase B (Akt) and p-mammalian target of rapamycin signaling (mTOR) in the HG groups were increased compared with the control group. However, following Akt inhibition with 1.0 or 10.0 nM MK-2206, which is an Akt-specific small molecule inhibitor, the senescence-cell value in the HG group was significantly decreased compared with the control group. These results indicated that HG induced MSCs senescence and this effect was primarily mediated via the Akt/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

Zhang

Chen

et al. 2017

Molecular Medicine Reports

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“…Several studies had shown that MSCs preferentially homed to the sites of tissue damages, where they enhanced wound healing, and involved in modulating the balance of in ammatory response [21]. To determine whether Wip1 −/− MSCs could migrate to the damage sides in pancreas, red uorescence stained Wip1 −/− MSCs and Wip1 +/+ MSCs were administrated into T1DM mice.…”

Section: Ifn-α Secreted By Wip1 −/− Mscs Aggravated In Ammatory Respomentioning

confidence: 99%

Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2

Zhou

Liu

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) shows significant therapeutic effects in type 1 diabetes mellitus (T1DM) as they could regulate the inflammatory processes. However, little is known about the process of MSCs immunosuppression in T1DM. In this study, we investigated the effects of wild type p53-induce phosphatase 1 (Wip1) on regulating MSCs immunosuppressive capacities in T1DM mice.Methods: Primary wild type (Wip1+/+) MSCs and Wip1 knockout (Wip1−/−) MSCs were cultured in vitro. T1DM mouse model was induced with streptozotocin and then was treated with Wip1+/+ MSCs (5 × 105) or Wip1−/− MSCs (5 × 105) by tail vein injection. The general physiological states of T1DM mice were measured every week. Moreover, the pathological changes in the pancreatic tissue were observed. Enzyme-linked immunosorbent assay (ELISA) and flow cytometry were used to detect the expressions of inflammatory cytokines in mice.Results: Wip1 −/− MSCs had lower therapeutic effects in T1DM mice. Moreover, we screened and confirmed bone marrow stromal cell antigen2 (BST2) gene that showed the target gene for Wip1 through gene chips, quantitative polymerase chain reaction and Western blot. Wip1−/− MSCs exhibited lower immunosuppressive capacity, as evidenced by enhanced expression of BST2, with concurrent increased expression of interferon-α (IFN-α). In vivo distribution analysis results indicated that Wip1−/− MSCs homed to the damaged pancreatic tissue. Wip1−/− MSCs influenced the expression of immune factors by remarkably increasing the expression of tumor necrosis factor-α (TNF-α), interleukin-17A (IL-17A), IFN-α, IFN-β, and IFN-γ and decreasing the expression of IL-4 and IL-10.Conclusions: Wip1 affects MSCs immunomodulation by regulating the expression of IFN-α/BST2. These findings suggest that Wip1 is required to regulate the therapeutic effects of MSCs on T1DM treatment, indicating a novel role of Wip1 in immunoregulation.

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“…They have been shown to be safe for application in patients [22][23][24]. Furthermore, as enhancers of epigenetic signals, HDACi have been applied to modulate cell differentiation in vitro [25][26][27][28]. In this work, we examined the effects of LBH589 and class I-specific HDACi MS-275 and MGCD103 on gene transcription in human mesenchymal bone-marrow derived stem cells.…”

Section: Introductionmentioning

confidence: 99%

Class I and II Histone Deacetylase Inhibitor LBH589 Promotes Endocrine Differentiation in Bone Marrow Derived Human Mesenchymal Stem Cells and Suppresses Uncontrolled Proliferation

Schröder

Khatri

Petry

et al. 2020

Exp Clin Endocrinol Diabetes

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Mesenchymal stem cells are useful tools employed in clinical and preclinical medicine. Their beneficial potential in especially degenerative as well as autoimmune diseases is a constant focus of research. Regarding diabetes mellitus, transplantation of stem cells is seen as a possible therapeutic approach to overcome the loss of endocrine pancreatic cells. It was reported that co-transplantation of mesenchymal stem cells with pancreatic islet cells improves function and survival of the graft. However, these multipotent progenitors may be able to form tumors, especially under immunosuppressed conditions. Histone deacetylase inhibitors might offer the potential to overcome this issue. These small molecules can induce cell differentiation and control proliferation. Their potential to control lineage development of stem cells has been distinctly demonstrated in the treatment of cancer, mainly in hematopoietic neoplasias.In this study, we demonstrate that human bone marrow-derived mesenchymal stem cells exhibit low carcinogenic potential in an immunosuppressed condition in vivo. Further, the effect of histone deacetylase inhibitors LBH589, MS-275, and MGCD0103 was examined after normalizing histone deacetylase activities in culture. Interestingly, transcripts of insulin gene enhancer protein and paired-box-gene 6, two markers of pancreatic endocrine differentiation were constitutively expressed in the cell line. The broad spectrum inhibitor of class I and class II histone deacetylases LBH589 upregulated the expression of these transcription factors in a significant way, whereas addition of selective class I histone deacetylase inhibitors MS-275 and MGCD0103 did not result in significant changes in gene expression.In conclusion, we deliver evidence that a combined class I and II histone deacetylase inhibition is able to modulate the transcripts of differentiation markers of mesenchymal stem cells. The treatment holds the capability to facilitate endocrine differentiation in future approaches to replace endocrine cells by stem cell therapy.

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Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells

Cited by 25 publications

References 205 publications

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2

Class I and II Histone Deacetylase Inhibitor LBH589 Promotes Endocrine Differentiation in Bone Marrow Derived Human Mesenchymal Stem Cells and Suppresses Uncontrolled Proliferation

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